WO2020169472A2 - Procédés d'induction de changements phénotypiques dans des macrophages - Google Patents

Procédés d'induction de changements phénotypiques dans des macrophages Download PDF

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WO2020169472A2
WO2020169472A2 PCT/EP2020/053906 EP2020053906W WO2020169472A2 WO 2020169472 A2 WO2020169472 A2 WO 2020169472A2 EP 2020053906 W EP2020053906 W EP 2020053906W WO 2020169472 A2 WO2020169472 A2 WO 2020169472A2
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tumor
cancer
syndrome
cell
disease
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WO2020169472A3 (fr
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Toby Lawrence
Pieter GOOSSENS
Juan RODRIGUEZ VITA
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université D'aix Marseille
Centre National De La Recherche Scientifique (Cnrs)
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    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
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    • C12N2502/30—Coculture with; Conditioned medium produced by tumour cells

Definitions

  • the field of the invention is immunology.
  • TAM tumor-associated macrophages
  • tissue-resident macrophages In mammals, macrophages are found in all tissues after birth and are endowed with trophic functions that contribute to organ development and remodelling (Pollard, 2009). Recent advances in genetic fate-mapping techniques have revealed that the majority of tissue-resident macrophages, at least in steady-state, develop from embryonic precursors and are maintained by local proliferation with little input from hematopoeitc stem cells (HSC) in the bone marrow (Schulz et al., 2012). Subsequent studies have shown that embryonic macrophages can be gradually replaced by HSC-derived blood monocytes, to varying degrees depending on the specific context (Ginhoux and Guilliams, 2016). But the functional implications of these distinct developmental origins and certainly their respective contributions to tumor progression remain unclear. In a recent study, both tissue-resident macrophages of embryonic origin and monocyte-derived TAM were shown to contribute towards tumor growth in a mouse model of pancreatic cancer (Zhu et al., 2017).
  • tissue-resident macrophages The phenotype of tissue-resident macrophages is dictated by the tissue-specific signals in their respective niche (Gosselin et al, 2014; Lavin et al., 2014). However, during inflammation or tissue stress, monocyte-derived macrophages can be recruited into tissues and their functional reprogramming is dictated by the pathological context. It is now widely appreciated that macrophages follow a multi-dimensional model of activation states with distinct phenotypic and functional properties in response to different stimuli in the tissue microenvironment and can maintain considerable plasticity (Murray et al, 2014; Xue et al.,
  • TAM in various experimental models and human cancers have been shown to express uniques sets of gene patterns including the production of specific chemokines, cytokines and growth factors linked with tumor progression, such as CCL2, TNF, VEGF, basic fibroblast growth factor (bFGF) and matrix metalloproteinases (MMPs) (Kratochvill et al.,
  • TAM are invariably reprogrammed towards a functional state that supports tumor growth and immune-suppression and away from inflammatory phenotypes that could be associated with anti-tumor functions.
  • the specific mechanisms that drive TAM accumulation and polarization in different tumors remain unclear.
  • Several studies have shown that TAM are CSF-1 dependent, as are most tissue macrophages, and CSF-1 signaling has been suggested to be an important factor in their reprogramming towards pro-tumor functions (Martinez et al., 2006; Noy and Pollard, 2014).
  • CSF-1 and IL-4 signaling in TAM was later shown to cooperatively promote growth of lung metastatses in the MMTV-pyMT mouse model of mammary carcinonogenesis (DeNardo et al, 2009).
  • primary tumor- development in this model was CSF-1 dependent (Lin et al., 2006)
  • IL-4 signaling in TAM did not impact primary tumors (DeNardo et al, 2009).
  • Subsequent studies showed that the development of lung metastases, but not primary tumors, in the same model critically requires the recruitment of CCR2-dependent monocytes (Qian et al., 2011). Suggesting that IL-4 signaling, specifically in monocyte-derived TAM, promotes metastatic disease in this model.
  • the present relates to a method of inducing a phenotypic change in a population of macrophages in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an agent that modulates cholesterol efflux in said population of macrophages.
  • TAM Tumor-associated macrophages
  • TAM Tumor-associated macrophages
  • cytotoxic lymphocytes have been shown to have important roles in the malignant progression of various cancers.
  • macrophages also possess intrinsic tumoricidal activity and can promote the activity of cytotoxic lymphocytes, but they rapidly adopt an alternative phenotype within tumors, associated with immune-suppression and trophic functions that support tumor growth.
  • the mechanisms that promote TAM polarization in the tumor-microenvironment remain poorly understood, these mechanisms may represent important therapeutic targets to block the tumor-promoting functions of TAM and restore their anti-tumor potential.
  • the inventors have characterized TAM in a mouse model of metastatic ovarian cancer. They show that ovarian cancer cells promote membrane-cholesterol efflux and the depletion of lipid rafts from macrophages.
  • the first object of the present invention relates to a method of inducing a phenotypic change in a population of macrophages in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an agent that modulates cholesterol efflux in said population of macrophages.
  • macrophage has its general meaning in the art and refers to a type of antigen-presenting cell of the mammalian immune system that have phagocytic activities. These cells are characterized by their distinctive morphology and high levels of surface MHC-class II expression.
  • a macrophage is a monocyte-derived phagocyte which is not a dendritic cell or a cell that derives from tissue macrophages by local proliferation. In the body these cells are tissue specific and refer to e. g. Kupffer cells in the liver, alveolar macrophages in the lung, microglia cells in the brain, osteoclasts in the bone etc.
  • the skilled person is aware how to identify macrophage cells, how to isolate macrophage cells from the body of a human or animal, and how to characterize macrophage cells with respect to their subclass and subpopulation.
  • Macrophages have historically been divided into two phenotypically diverse populations, i.e. a Ml -polarized or "classically activated” population, and a macrophage M2 - polarized or “alternatively activated” population.
  • Ml -polarized or “classically activated” population a macrophage M2 - polarized or “alternatively activated” population.
  • Macrophages exhibiting a Ml phenotype are pro-inflammatory, and are capable of either direct (pathogen pattern recognition receptors) or indirect (Fc receptors, complement receptors) recognition of pathogens and tumor antigens (i.e. they exhibit anti -tumor activity).
  • Ml macrophages produce reactive oxygen species and secrete pro-inflammatory cytokines and chemokines, such as, for example, but without limitation, TNFa, IL-1, IL-6, IL-15, IL-18, IL- 23, and iNOS.
  • Ml macrophages also express high levels of MHC, costimulatory molecules, and FCyR.
  • the Ml phenotype is triggered by GM-CSF and further stimulated by interferon-g (IFN-g), bacterial lipopolysaccharide (LPS), or tumor necrosis factor a (TNFa), and is mediated by several signal transduction pathways involving signal transducer and activator of transcription (STAT), nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB), and mitogen-activated protein kinases (MAPK).
  • IFN-g interferon-g
  • LPS bacterial lipopolysaccharide
  • TNFa tumor necrosis factor a
  • STAT signal transducer and activator of transcription
  • NFKB nuclear factor kappa-light-chain-enhancer of activated B cells
  • MAPK mitogen-activated protein kinases
  • macrophages exhibiting a M2 phenotype are often characterized as being anti-inflammatory and immunosuppressive as they suppress T-cell responses and are involved in the Th2-type immune response.
  • the M2 macrophage phenotype facilitates tissue repair, wound healing, and is profibrotic.
  • M2 macrophages often undesirably infiltrate and surround tumors, where they provide an immunosuppressive microenvironment that promotes rather than suppresses tumor progression.
  • M2 macrophages are characterized by high surface expression of I1-4R, FcsR, Dectin-1, CD 136, CD206, and CD209A.
  • M2 macrophages include IL-4/IL- 13 -stimulated macrophages, IL-10-induced macrophages, and immune complex-triggered macrophages.
  • the method of the present invention is thus suitable for inducing one or more phenotypic changes in a population of macrophages to adjust a population of macrophages to have a desired phenotype, e.g. a pro-inflammatory phenotype (Ml) or an immunosuppressive phenotype (M2).
  • a desired phenotype e.g. a pro-inflammatory phenotype (Ml) or an immunosuppressive phenotype (M2).
  • a "phenotypic change” encompasses an observable or detectable change in a characteristic, property, attribute, or function of the population of macrophages.
  • phenotypic characteristics/properties/functions of macrophages that can be modified or modulated in accordance with the methods of the present invention include, without limitation, pro-inflammatory activity, anti-inflammatory activity, immunogenic activity, tolerogenic activity, tissue damaging activity, tissue healing activity, cytotoxic activity, migratory activity, bone-resorbing activity, angiogenic activity, anti- angiogenic activity, suppressor activity, antigen presenting activity, or phagocytic activity.
  • a phenotypic change in the macrophages may be observed or detected in any of a number of ways.
  • a phenotypic change may be observed or detected either by performing a test, observation, or measurement on the macrophages themselves or by performing a test, observation, or measurement, on other cells, tissues, organs, etc., that may be affected by the monocytes/macrophages, or by performing a test, observation, or measurement on a subj ect that contains the phenotypically modified macrophages.
  • Phenotypic change or modulation can be assessed by detecting or measuring, for example, (i) a change in the expression of one or more genes (e.g., cytokines, inflammatory mediators, etc.); (ii) the change in secretion of one or more molecules (e.g., cytokines, inflammatory mediators, etc.); (iii) an increase or decrease in migration to one or more sites in the body; (iv) a change in the ability to cause an alteration in one or more phenotypic characteristics or phenotypes of another macrophage-related cell or ability to cause an alteration in one or more phenotypic characteristics or phenotypes of a non-macrophage-related cell.
  • genes e.g., cytokines, inflammatory mediators, etc.
  • the change in secretion of one or more molecules e.g., cytokines, inflammatory mediators, etc.
  • an increase or decrease in migration to one or more sites in the body i
  • RNA level can be assessed at the RNA level using cDNA or oligonucleotide microarray analysis, Northern blots, RT-PCR, sequencing, etc.
  • Protein expression can be measured using, for example, immunoblotting, immunohistochemistry, protein microarrays, etc.
  • cell-based assays and animal models readily known and utilized in the art can also be used.
  • the method of the present invention is particularly suitable for inducing a phenotypic change in a population of tumor-associated macrophages (TAM). More specifically, the method of the present invention is particularly suitable for blocking pro-tumor functions and restoring anti-tumor immunity of tumor-associated macrophages.
  • TAM tumor-associated macrophages
  • TAM tumor associated macrophage
  • TAMs are derived from circulating monocytes or resident tissue macrophages, which form the major leukocytic infiltrate found within the stroma of many tumor types. TAM are characterized by the expression of CD 163.
  • the term“cholesterol efflux” or“cholesterol efflux activity” refers to the efflux of cholesterol from population of macrophages as described in the EXAMPLE. Accordingly the term refers to the movement of cholesterol from the cell to the cell's exterior.
  • the term “modulate” when applied to the term“cholesterol efflux” refers to an increase or a decrease in said cholesterol efflux.
  • the agent can be an agent that increases said cholesterol efflux or an agent that decreases said cholesterol efflux.
  • the increase can be at least about 10%, e.g., at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 100%, 150%, 200%. 250%. 300%, 400%, 500% or more.
  • the decrease can be at least about 10%, e.g., at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more.
  • the term "decrease” thus includes the inhibition or blockage of said cholesterol efflux.
  • the term“agent” refers to any chemical entity, including, without limitation, a glycomer, a protein, an antibody, a lectin, a nucleic acid, a small molecule, and any combination thereof.
  • agents include, but are not limited to, a ribozyme, a DNAzyme and a siRNA molecule.
  • the agent is an antibody.
  • antibody has its general meaning in the art and encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, human antibodies, humanized antibodies, camelised antibodies, chimeric antibodies, single chain Fvs (scFv), single-chain antibodies, single domain antibodies, domain antibodies, Fab fragments, F(ab')2 fragments, antibody fragments that exhibit the desired biological activity, disulfide-linked Fvs (sdFv), and anti-idiotypic (anti-id) antibodies (including, e.g., anti-id antibodies to antibodies of the invention), intrabodies, and epitope-binding fragments of any of the above.
  • monoclonal antibodies including full-length monoclonal antibodies
  • polyclonal antibodies multispecific antibodies formed from at least two intact antibodies, human antibodies, humanized antibodies, camelised antibodies, chimeric antibodies, single chain Fvs (scFv), single-chain antibodies,
  • antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site.
  • Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGI, IgG2, IgG3, IgG4, IgAI and IgA2) or subclass.
  • the antibody of the present invention is a monoclonal antibody.
  • the term“monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody preparations which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.
  • monoclonal antibodies are advantageous in that they can be synthesized by hybridoma cells that are uncontaminated by other immunoglobulin producing cells.
  • Alternative production methods are known to those trained in the art, for example, a monoclonal antibody may be produced by cells stably or transiently transfected with the heavy and light chain genes encoding the monoclonal antibody.
  • Monoclonal antibodies may be generated using the method of Kohler and Milstein (Nature, 256:495, 1975).
  • a mouse or other appropriate host animal is immunized at suitable intervals (e.g., twice-weekly, weekly, twice-monthly or monthly) with the appropriate antigenic forms (i.e. polypeptides of the present invention).
  • the animal may be administered a final "boost" of antigen within one week of sacrifice. It is often desirable to use an immunologic adjuvant during immunization.
  • Suitable immunologic adjuvants include Freund's complete adjuvant, Freund's incomplete adjuvant, alum, Ribi adjuvant, Hunter's Titermax, saponin adjuvants such as QS21 or Quil A, or CpG- containing immunostimulatory oligonucleotides.
  • Other suitable adjuvants are well-known in the field.
  • the animals may be immunized by subcutaneous, intraperitoneal, intramuscular, intravenous, intranasal or other routes. A given animal may be immunized with multiple forms of the antigen by multiple routes.
  • the recombinant polypeptide of the present invention may be provided by expression with recombinant cell lines.
  • Recombinant forms of the polypeptides may be provided using any previously described method.
  • lymphocytes are isolated from the spleen, lymph node or other organ of the animal and fused with a suitable myeloma cell line using an agent such as polyethylene glycol to form a hydridoma.
  • cells are placed in media permissive for growth of hybridomas but not the fusion partners using standard methods.
  • cell supernatants are analysed for the presence of antibodies of the desired specificity, i.e., that selectively bind the antigen.
  • Suitable analytical techniques include ELISA, flow cytometry, immunoprecipitation, and western blotting. Other screening techniques are well-known in the field.
  • Preferred techniques are those that confirm binding of antibodies to conformationally intact, natively folded antigen, such as non-denaturing ELISA, flow cytometry, and immunoprecipitation.
  • the monoclonal antibody of the invention is a chimeric antibody, in particular a chimeric mouse/human antibody.
  • the term "chimeric antibody” refers to an antibody which comprises a VH domain and a VL domain of a non-human antibody, and a CH domain and a CL domain of a human antibody.
  • the human chimeric antibody of the present invention can be produced by obtaining nucleic sequences encoding VL and VH domains as previously described, constructing a human chimeric antibody expression vector by inserting them into an expression vector for animal cell having genes encoding human antibody CH and human antibody CL, and expressing the coding sequence by introducing the expression vector into an animal cell.
  • CH domain of a human chimeric antibody it may be any region which belongs to human immunoglobulin, but those of IgG class are suitable and any one of subclasses belonging to IgG class, such as IgGl, IgG2, IgG3 and IgG4, can also be used.
  • CL of a human chimeric antibody it may be any region which belongs to Ig, and those of kappa class or lambda class can be used.
  • the monoclonal antibody of the invention is a humanized antibody.
  • the variable domain comprises human acceptor frameworks regions, and optionally human constant domain where present, and non human donor CDRs, such as mouse CDRs.
  • the term "humanized antibody” refers to an antibody having variable region framework and constant regions from a human antibody but retains the CDRs of a previous non-human antibody.
  • the humanized antibody of the present invention may be produced by obtaining nucleic acid sequences encoding CDR domains, as previously described, constructing a humanized antibody expression vector by inserting them into an expression vector for animal cell having genes encoding (i) a heavy chain constant region identical to that of a human antibody and (ii) a light chain constant region identical to that of a human antibody, and expressing the genes by introducing the expression vector into an animal cell.
  • the humanized antibody expression vector may be either of a type in which a gene encoding an antibody heavy chain and a gene encoding an antibody light chain exists on separate vectors or of a type in which both genes exist on the same vector (tandem type).
  • humanized antibody expression vector of the tandem type In respect of easiness of construction of a humanized antibody expression vector, easiness of introduction into animal cells, and balance between the expression levels of antibody H and L chains in animal cells, humanized antibody expression vector of the tandem type is preferred.
  • tandem type humanized antibody expression vector include pKANTEX93 (WO 97/10354), pEE18 and the like.
  • Antibodies can be humanized using a variety of techniques known in the art including, for example, CDR-grafting (EP 239,400; PCT publication WO91/09967; U.S. Pat. Nos. 5,225,539; 5,530,101; and 5,585,089), veneering or resurfacing (EP 592,106; EP 519,596; Padlan EA (1991); Studnicka GM et al. (1994); Roguska MA. et al. (1994)), and chain shuffling (U.S. Pat. No.5, 565, 332).
  • the general recombinant DNA technology for preparation of such antibodies is also known (see European Patent Application EP 125023 and International Patent Application WO 96/02576).
  • the antibody of the invention is a human antibody.
  • human antibody is intended to include antibodies having variable and constant regions derived from human immunoglobulin sequences.
  • the human antibodies of the present invention may include amino acid residues not encoded by human immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • the term "human antibody”, as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk and van de Winkel, cur. Opin.
  • Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge.
  • Such animals typically contain all or a portion of the human immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes. In such transgenic mice, the endogenous immunoglobulin loci have generally been inactivated.
  • Phage display techniques mimic immune selection through the display of antibody repertoires on the surface of filamentous bacteriophage, and subsequent selection of phage by their binding to an antigen of choice.
  • One such technique is described in PCT publication No. WO 99/10494.
  • Human antibodies described herein can also be prepared using SCID mice into which human immune cells have been reconstituted such that a human antibody response can be generated upon immunization. Such mice are described in, for example, U.S. Patent Nos. 5,476,996 and 5,698,767 to Wilson et al.
  • the agent that modulates the cholesterol efflux is an agent that modulates the activity or expression of a cholesterol efflux mediating protein.
  • cholesterol efflux-mediating protein refers to any protein which, when properly situated in and/or on a macrophage, facilitates the efflux of cholesterol from the macrophage.
  • a“cholesterol efflux-mediating protein” include, without limitation, ABCl, ABCGl and ABCG4.
  • the agent that modulates the cholesterol efflux is an agent that modulates the activity or expression of ABCl, ABCGl and ABCG4.
  • ABCl has its general meaning in the art and refers to the ATP -binding cassette sub-family A member 1.
  • An exemplary human amino acid sequence is represented by SEQ ID NO: 1.
  • the extracellular domain of ABCl corresponds to the amino acid sequence that ranges from amino acid residue at position 43 to the amino acid residue at position 639 in SEQ ID NO: 1.
  • ABC1 has its general meaning in the art and refers to the ATP -binding cassette sub-family G member 1.
  • An exemplary human amino acid sequence is represented by SEQ ID NO: 2.
  • the extracellular domain of ABC1 corresponds to the amino acid sequence that ranges from amino acid residue at position 446 to the amino acid residue at position 456 in SEQ ID NO:2.
  • ABC4 has its general meaning in the art and refers to the ATP -binding cassette sub-family G member 4.
  • An exemplary human amino acid sequence is represented by SEQ ID NO: 3.
  • the extracellular domain of ABC1 corresponds to the amino acid sequence that ranges from amino acid residue at position 415 to the amino acid residue at position 425 in SEQ ID NO:3.
  • the agent that modulates the activity of ABC1, ABCG1 or ABCG4 is an antibody that binds to the extracellular domain of ABC1, ABCG1 or ABCG4 respectively.
  • the agent that modulates the cholesterol efflux is an agent that modulates the activity or expression of a receptor for hyaluronic acid.
  • hyaluronic acid or“HA” refers to the polymer having the formula:
  • n is the number of repeating units.
  • All sources of hyaluronic acid are useful in this invention, including bacterial and avian sources.
  • Hyaluronic acids useful in this invention have a molecular weight superior to lOOkDa (“high molecular weight”).
  • the agent that modulates the the cholesterol efflux modulates the activity or expression of CD44 or Lyve-1 that are receptors for HA.
  • CD44 has its general meaning in the art and refers to a receptor for hyaluronic acid.
  • the term is also known as CDw44, Epican, Extracellular matrix receptor III (ECMR-III), GP90 lymphocyte homing/adhesion receptor, HUTCH-I, Heparan sulfate proteoglycan, Hermes antigen, Hyaluronate receptor, Phagocytic glycoprotein 1 (PGP- 1), and Phagocytic glycoprotein I (PGP-I).
  • An exemplary human amino acid sequence is represented by SEQ ID NO:4.
  • the extracellular domain of CD44 corresponds to the amino acid sequence that ranges from amino acid residue at position 21 to the amino acid residue at position 649 in SEQ ID NO:4.
  • Lyve-1 has its general meaning in the art and refers to the lymphatic vessel endothelial hyaluronic acid receptor 1.
  • An exemplary human amino acid sequence is represented by SEQ ID NO: 5.
  • the extracellular domain of CD44 corresponds to the amino acid sequence that ranges from amino acid residue at position 20 to the amino acid residue at position 238 in SEQ ID NO: 5.
  • the agent modulates the activity of CD44 or Lyve-1 is an antibody that binds to the extracellular domain of CD44 or Lyve-1.
  • the agent is an inhibitor of expression; such as an inhibitor of. ABC1, ABCG1, ABCG4, CD44 or Lyve-1 expression.
  • the agent that modulates the cholesterol efflux is an inhibitor of expression of ABC1, ABCG1, ABCG4 CD44 or Lyve-1.
  • An“inhibitor of expression” refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene.
  • said inhibitor of gene expression is a siRNA, an antisense oligonucleotide or a ribozyme.
  • anti-sense oligonucleotides including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of Proprotein convertase (PC) mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of Proprotein convertase (PC), and thus activity, in a cell.
  • antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding Proprotein convertase (PC) can be synthesized, e.g., by conventional phosphodiester techniques.
  • Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well known in the art (e.g.
  • Small inhibitory RNAs can also function as inhibitors of expression for use in the present invention.
  • Proprotein convertase (PC) gene expression can be reduced by contacting a patient or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that Proprotein convertase (PC) gene expression is specifically inhibited (i.e. RNA interference or RNAi).
  • Antisense oligonucleotides, siRNAs, shRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector.
  • a "vector” is any vehicle capable of facilitating the transfer of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid to the cells and typically cells expressing Proprotein convertase (PC).
  • PC Proprotein convertase
  • the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector.
  • the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid sequences.
  • Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus; adenovirus, adeno- associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus.
  • retrovirus such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus
  • adenovirus adeno- associated virus
  • SV40-type viruses polyoma viruses
  • Epstein-Barr viruses papilloma viruses
  • herpes virus vaccinia virus
  • polio virus poli
  • the term“endonuclease” refers to enzymes that cleave the phosphodiester bond within a polynucleotide chain. Some, such as Deoxyribonuclease I, cut DNA relatively nonspecifically (without regard to sequence), while many, typically called restriction endonucleases or restriction enzymes, and cleave only at very specific nucleotide sequences.
  • the mechanism behind endonuclease-based genome inactivating generally requires a first step of DNA single or double strand break, which can then trigger two distinct cellular mechanisms for DNA repair, which can be exploited for DNA inactivating: the errorprone nonhomologous end-joining (NHEJ) and the high-fidelity homology-directed repair (HDR).
  • NHEJ errorprone nonhomologous end-joining
  • HDR high-fidelity homology-directed repair
  • the endonuclease is CRISPR-cas.
  • CRISPR- cas has its general meaning in the art and refers to clustered regularly interspaced short palindromic repeats associated which are the segments of prokaryotic DNA containing short repetitions of base sequences.
  • the endonuclease is CRISPR-cas9 which is from Streptococcus pyogenes. The CRISPR/Cas9 system has been described in US 8697359 B1 and US 2014/0068797.
  • the endonuclease is CRISPR-Cpfl which is the more recently characterized CRISPR from Provotella and Francisella 1 (Cpfl) in Zetsche et al. (“Cpfl is a Single RNA-guided Endonuclease of a Class 2 CRISPR-Cas System (2015); Cell; 163, 1-13).
  • the agent that modulates the cholesterol efflux is selected as depicted in Table A.
  • Table A examples of agents capable of modulating cholesterol efflux in macrophages.
  • the agent that modulates the cholesterol efflux is an agent that decreases the cholesterol efflux in macrophages.
  • the agent that decrease the cholesterol efflux in macrophages is an a antagonistic antibody that binds to the extracellular domain of ABC 1 , ABCG1 ABCG4, CD44 or Lyve-1 respectively
  • the agent that decrease the cholesterol efflux in macrophages is an inhibitor of expression of ABC1, ABCG1, ABCG4 CD44 or Lyve-1
  • the agent that modulates the cholesterol efflux is an agent that increases the cholesterol efflux in macrophages.
  • the agent that increase the cholesterol efflux in macrophages is an a agonistic antibody that binds to the extracellular domain of ABC1, ABCGl ABCG4, CD44 or Lyve-1 respectively
  • the agent that increase the cholesterol efflux in macrophages is a hyaluronic acid.
  • the method as described herein particularly suitable for the purpose of treating a disease or condition that is caused or exacerbated, at least in part, by macrophages exhibiting one or more undesirable phenotypes.
  • a further object of the present invention relates to a method of therapy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an agent that modulates cholesterol efflux in a population of macrophages.
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).
  • an agent that increases cholesterol efflux in a population of macrophages would be suitable for the treatment of autoimmune inflammatory disease.
  • Autoimmune inflammatory diseases typically involve the undesired actions of pro- inflammatory macrophages (Ml).
  • Ml pro- inflammatory macrophages
  • Using the method of the present invention to induce a macrophage M2 phenotypic change in the Ml pro-inflammatory macrophages that are involved in these diseases would be suitable for alleviating one or more symptoms of the diseases.
  • the autoimmune inflammatory disease is selected from the group consisting of arthritis, rheumatoid arthritis, acute arthritis, chronic rheumatoid arthritis, gouty arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, vertebral arthritis, and juvenile-onset rheumatoid arthritis, osteoarthritis, arthritis chronica progrediente, arthritis deformans, polyarthritis chronica primaria, reactive arthritis, and ankylosing spondylitis), inflammatory hyperproliferative skin diseases, psoriasis such as plaque psoriasis, gutatte psoriasis, pustular psoriasis, and psoriasis of the nails, dermatitis including contact dermatitis, chronic contact dermatitis, allergic dermatitis, allergic contact dermatitis, dermatitis herpetiformis, and atopic
  • an agent that supresses cholesterol efflux in a population of tumor-associated macrophages would be suitable for the treatment of cancer.
  • TAMs tumor-associated macrophages
  • TAMs tumor-associated macrophages
  • TGF transforming growth factor
  • TAMs promote tumor neo- angiogenesis by the secretion of pro-angiogenic factors and define the invasive microenvironment to facilitate tumor metastasis and dissemination. Therefore, employing the method of the present invention to induce a Ml phenotypic change in the TAMs to enhance anti-tumor immunity will significantly alter the progression of the cancer.
  • cancer has its general meaning in the art and includes, but is not limited to, solid tumors and blood-borne tumors.
  • the term cancer includes diseases of the skin, tissues, organs, bone, cartilage, blood and vessels.
  • the term “cancer” further encompasses both primary and metastatic cancers. Examples of cancers that may be treated by methods and compositions of the invention include, but are not limited to, cancer cells from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestinal tract, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus.
  • the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acid
  • the agent that decreases the cholesterol efflux would thus be suitable for enhancing the proliferation, migration, persistence and/or activity of cytotoxic T lymphocytes (CTLs).
  • CTLs cytotoxic T lymphocytes
  • a further of the present invention relates to a method of enhancing the proliferation, migration, persistence and/or activity of cytotoxic T lymphocytes (CTLs) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an agent that suppresses cholesterol efflux in TAM.
  • CTLs cytotoxic T lymphocytes
  • the term“cytotoxic T lymphocyte” or“CTL” has its general meaning in the art and refers to a subset of T cells which express CD8 on their surface.
  • CD8 antigens are members of the immunoglobulin supergene family and are associative recognition elements in major histocompatibility complex class I-restricted interactions. They are MHC class I- restricted, and function as cytotoxic T cells.
  • Cytotoxic T lymphocytes are also called, CD8+ T cells, T-killer cells, cytolytic T cells, or killer T cells.
  • the ability of the proprotein convertase (PC) inhibitor to enhance proliferation, migration, persistence and/or cytotoxic activity of cytotoxic T lymphocytes may be determined by any assay well known in the art.
  • said assay is an in vitro assay wherein cytotoxic T lymphocytes are brought into contact with target cells (e.g. target cells that are recognized and/or lysed by cytotoxic T lymphocytes).
  • the proprotein convertase (PC) inhibitor can be selected for the ability to increase specific lysis by cytotoxic T lymphocytes by more than about 20%, preferably with at least about 30%, at least about 40%, at least about 50%, or more of the specific lysis obtained at the same effector: target cell ratio with cytotoxic T lymphocytes that are contacted by the proprotein convertase (PC) inhibitor of the present invention.
  • PC proprotein convertase
  • Examples of protocols for classical cytotoxicity assays are conventional.
  • the administration of the agent that decreases the cholesterol efflux in TAM is combined with an immune checkpoint inhibitor.
  • immune checkpoint inhibitor has its general meaning in the art and refers to any compound inhibiting the function of an immune inhibitory checkpoint protein.
  • immuno checkpoint protein has its general meaning in the art and refers to a molecule that is expressed by T cells in that either turn up a signal (stimulatory checkpoint molecules) or turn down a signal (inhibitory checkpoint molecules).
  • Immune checkpoint molecules are recognized in the art to constitute immune checkpoint pathways similar to the CTLA-4 and PD-1 dependent pathways (see e.g. Pardoll, 2012. Nature Rev Cancer 12:252-264; Mellman et al. , 2011. Nature 480:480- 489).
  • inhibitory checkpoint molecules examples include A2AR, B7-H3, B7-H4, BTLA, CTLA-4, CD277, IDO, KIR, PD- 1, LAG-3, TIM-3 and VISTA. Inhibition includes reduction of function and full blockade.
  • Preferred immune checkpoint inhibitors are antibodies that specifically recognize immune checkpoint proteins. A number of immune checkpoint inhibitors are known and in analogy of these known immune checkpoint protein inhibitors, alternative immune checkpoint inhibitors may be developed in the (near) future.
  • the immune checkpoint inhibitors include peptides, antibodies, nucleic acid molecules and small molecules.
  • immune checkpoint inhibitor includes PD-1 antagonist, PD-L1 antagonist, PD-L2 antagonist CTLA-4 antagonist, VISTA antagonist, TIM-3 antagonist, LAG-3 antagonist, IDO antagonist, KIR2D antagonist, A2AR antagonist, B7-H3 antagonist, B7-H4 antagonist, and BTLA antagonist.
  • PD-1 (Programmed Death-1) axis antagonists include PD-1 antagonist (for example anti-PD-1 antibody), PD-L1 (Programmed Death Ligand-1) antagonist (for example anti-PD-Ll antibody) and PD-L2 (Programmed Death Ligand-2) antagonist (for example anti-PD-L2 antibody).
  • the anti-PD-1 antibody is selected from the group consisting of MDX-1106 (also known as Nivolumab, MDX-1106-04, ONO-4538, BMS-936558, and Opdivo®), Merck 3475 (also known as Pembrolizumab, MK-3475, Lambrolizumab, Keytruda®, and SCH-900475), and CT-011 (also known as Pidilizumab, hBAT, and hBAT-1).
  • the PD-1 binding antagonist is AMP-224 (also known as B7-DCIg).
  • the anti-PD-Ll antibody is selected from the group consisting of YW243.55.S70, MPDL3280A, MDX-1105, and MEDI4736.
  • MDX-1105 also known as BMS-936559, is an anti-PD-Ll antibody described in W02007/005874.
  • Antibody YW243.55. S70 is an anti-PD-Ll described in WO 2010/077634 Al .
  • MEDI4736 is an anti-PD- Ll antibody described in WO2011/066389 and US2013/034559.
  • MDX-1106 also known as MDX-1106-04, ONO-4538 or BMS-936558, is an anti-PD-1 antibody described in U.S. Pat. No.
  • Merck 3745 also known as MK-3475 or SCH-900475, is an anti-PD-1 antibody described in U.S. Pat. No. 8,345,509 and W02009/114335.
  • CT-011 Panizilumab
  • AMP-224 also known as B7-DCIg, is a PD-L2-Fc fusion soluble receptor described in W02010/027827 and WO2011/066342.
  • Atezolimumab is an anti-PD-Ll antibody described in U.S. Pat. No. 8,217,149.
  • Avelumab is an anti-PD-Ll antibody described in US 20140341917.
  • CA-170 is a PD-1 antagonist described in W02015033301 & WO2015033299.
  • Other anti-PD-1 antibodies are disclosed in U.S. Pat. No. 8,609,089, US 2010028330, and/or US 20120114649.
  • the PD-1 inhibitor is an anti-PD-1 antibody chosen from Nivolumab, Pembrolizumab or Pidilizumab.
  • PD-L1 antagonist is selected from the group comprising of Avelumab, BMS-936559, CA-170, Durvalumab, MCLA-145, SP142, STI-A1011, STIA1012, STI-A1010, STI-A1014, A110, KY1003 and Atezolimumab and the preferred one is Avelumab, Durvalumab or Atezolimumab.
  • CTLA-4 Cytotoxic T-Lymphocyte Antigen-4 antagonists are selected from the group consisting of anti-CTLA-4 antibodies, human anti-CTLA-4 antibodies, mouse anti-CTLA-4 antibodies, mammalian anti-CTLA-4 antibodies, humanized anti-CTLA- 4 antibodies, monoclonal anti-CTLA-4 antibodies, polyclonal anti-CTLA-4 antibodies, chimeric anti-CTLA-4 antibodies, MDX-010 (Ipilimumab), Tremelimumab, anti-CD28 antibodies, anti-CTLA-4 adnectins, anti-CTLA-4 domain antibodies, single chain anti-CTLA- 4 fragments, heavy chain anti-CTLA-4 fragments, light chain anti-CTLA-4 fragments, inhibitors of CTLA-4 that agonize the co-stimulatory pathway, the antibodies disclosed in PCT Publication No.
  • CTLA-4 antibodies are described in U.S. Pat. Nos. 5,811,097; 5,855,887; 6,051,227; and 6,984,720; in PCT Publication Nos. WO 01/14424 and WO 00/37504; and in U.S. Publication Nos. 2002/0039581 and 2002/086014.
  • Other anti-CTLA-4 antibodies that can be used in a method of the present invention include, for example, those disclosed in: WO 98/42752; U.S. Pat.
  • a preferred clinical CTLA-4 antibody is human monoclonal antibody (also referred to as MDX-010 and Ipilimumab with CAS No.
  • CTLA-4 antagonist antibodies
  • Tremelimumab CP- 675,206
  • Ipilimumab Ipilimumab
  • immune-checkpoint inhibitors include lymphocyte activation gene-3 (LAG-3) inhibitors, such as IMP321, a soluble Ig fusion protein (Brignone et al., 2007, J. Immunol. 179:4202-4211).
  • Other immune-checkpoint inhibitors include B7 inhibitors, such as B7-H3 and B7-H4 inhibitors.
  • the anti-B7-H3 antibody MGA271 (Loo et al, 2012, Clin. Cancer Res. July 15 (18) 3834).
  • TIM-3 T-cell immunoglobulin domain and mucin domain 3) inhibitors (Fourcade et al., 2010, J. Exp. Med. 207:2175-86 and Sakuishi et al, 2010, J.
  • the term“TIM-3” has its general meaning in the art and refers to T cell immunoglobulin and mucin domain-containing molecule 3.
  • the natural ligand of TIM-3 is galectin 9 (Gal9).
  • the term“TIM-3 inhibitor” as used herein refers to a compound, substance or composition that can inhibit the function of TIM-3.
  • the inhibitor can inhibit the expression or activity of TIM-3, modulate or block the TIM-3 signaling pathway and/or block the binding of TIM-3 to galectin-9.
  • Antibodies having specificity for TIM-3 are well known in the art and typically those described in WO2011155607, WQ2013006490 and WO2010117057.
  • the immune checkpoint inhibitor is an IDO inhibitor.
  • IDO inhibitors are described in WO 2014150677.
  • IDO inhibitors include without limitation 1 -methyl-tryptophan (IMT), b- (3-benzofuranyl)-alanine, b-(3- benzo(b)thienyl)-alanine), 6-nitro-tryptophan, 6- fluoro-tryptophan, 4-methyl-tryptophan, 5 - methyl tryptophan, 6-methyl-tryptophan, 5-methoxy-tryptophan, 5 -hydroxy-tryptophan, indole 3-carbinol, 3,3'- diindolylmethane, epigallocatechin gallate, 5-Br-4-Cl-indoxyl 1,3- diacetate, 9- vinylcarbazole, acemetacin, 5-bromo-tryptophan, 5-bromoindoxyl diacetate, 3- Amino-naphtoic acid, pyr
  • the IDO inhibitor is selected from 1 -methyl-tryptophan, b-(3- benzofuranyl)-alanine, 6-nitro-L- tryptophan, 3- Amino-nap htoic acid and b-[3- benzo(b)thienyl] -alanine or a derivative or prodrug thereof.
  • the administration of the agent that decreases the cholesterol efflux in TAM is combined with a T-cell immunotherapy to boost the patient's anti-tumor immune response.
  • Suitable T-cell immunotherapies include, without limitation, adoptive T-cell therapy, tumor-infiltrating lymphocyte therapy, chimeric antigen receptor (CAR) T-cell therapy, and antigen-specific T-cell receptor transduced T-cell therapy.
  • CAR-T cell refers to a T lymphocyte that has been genetically engineered to express a CAR.
  • CAR T-cells encompasses all classes and subclasses of T-lymphocytes including CD4+ , CD8+ T cells, gamma delta T cells as well as effector T cells, memory T cells, regulatory T cells, and the like.
  • the T lymphocytes that are genetically modified may be "derived” or “obtained” from the subject who will receive the treatment using the genetically modified T cells or they may "derived” or “obtained” from a different subject.
  • a“Chimeric Antigen Receptor” or alternatively a“CAR” refers to a set of polypeptides, typically two in the simplest embodiments, which when in an immune effector cell, provides the cell with specificity for a target cell, typically a cancer cell, and with intracellular signal generation.
  • a CAR comprises at least an extracellular antigen binding domain, a transmembrane domain and a cytoplasmic signaling domain (also referred to herein as“an intracellular signaling domain”) comprising a functional signaling domain derived from a stimulatory molecule and/or costimulatory molecule as defined below.
  • the set of polypeptides are contiguous with each other.
  • the set of polypeptides include a dimerization switch that, upon the presence of a dimerization molecule, can couple the polypeptides to one another, e.g., can couple an antigen binding domain to an intracellular signaling domain.
  • the stimulatory molecule is the zeta chain associated with the T cell receptor complex.
  • the cytoplasmic signaling domain further comprises one or more functional signaling domains derived from at least one costimulatory molecule as defined below.
  • the costimulatory molecule is chosen from the costimulatory molecules described herein, e.g., 4-1BB (i.e., CD137), CD27 and/or CD28.
  • the CAR comprises a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain comprising a functional signaling domain derived from a stimulatory molecule. In some embodiments, the CAR comprises a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain comprising a functional signaling domain derived from a costimulatory molecule and a functional signaling domain derived from a stimulatory molecule.
  • the CAR comprises a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain comprising two functional signaling domains derived from one or more costimulatory molecule(s) and a functional signaling domain derived from a stimulatory molecule. In some embodiments, the CAR comprises a chimeric fusion protein comprising an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain comprising at least two functional signaling domains derived from one or more costimulatory molecule(s) and a functional signaling domain derived from a stimulatory molecule.
  • the CAR comprises an optional leader sequence at the amino-terminus (N-ter) of the CAR fusion protein.
  • the CAR further comprises a leader sequence at the N-terminus of the extracellular antigen binding domain, wherein the leader sequence is optionally cleaved from the antigen binding domain (e.g., a scFv) during cellular processing and localization of the CAR to the cellular membrane.
  • CARs comprise fusions of single-chain variable fragments (scFv) derived from monoclonal antibodies, fused to CD3-zeta a transmembrane domain and endodomain.
  • CARs comprise domains for additional co-stimulatory signaling, such as CD3-zeta, FcR, CD27, CD28, CD137, DAPIO, and/or 0X40.
  • molecules can be co-expressed with the CAR, including co-stimulatory molecules, reporter genes for imaging (e.g., for positron emission tomography), gene products that conditionally ablate the T cells upon addition of a pro-drug, homing receptors, chemokines, chemokine receptors, cytokines, and cytokine receptors.
  • the terms“combined treatment”, “combined therapy” or“therapy combination” refer to a treatment that uses more than one medication. The combined therapy may be dual therapy or bi-therapy.
  • Such administration may be simultaneous, separate or sequential.
  • the agents may be administered as one composition or as separate compositions, as appropriate.
  • the term“administration simultaneously” refers to administration of 2 active ingredients by the same route and at the same time or at substantially the same time.
  • the term“administration separately” refers to an administration of 2 active ingredients at the same time or at substantially the same time by different routes.
  • administration sequentially refers to an administration of 2 active ingredients at different times, the administration route being identical or different
  • the term "therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.
  • a therapeutically effective amount of the agent of the present invention may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the agent of the present invention to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.
  • the efficient dosages and dosage regimens for the agent of the present invention depend on the disease or condition to be treated and may be determined by the persons skilled in the art. A physician having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • a suitable dose of a composition of the present invention will be that amount of the compound, which is the lowest dose effective to produce a therapeutic effect according to a particular dosage regimen. Such an effective dose will generally depend upon the factors described above.
  • a therapeutically effective amount for therapeutic use may be measured by its ability to stabilize the progression of disease.
  • the ability of a compound to inhibit cancer may, for example, be evaluated in an animal model system predictive of efficacy in human tumors.
  • a therapeutically effective amount of a therapeutic compound may decrease tumor size, or otherwise ameliorate symptoms in a patient.
  • One of ordinary skill in the art would be able to determine such amounts based on such factors as the patient's size, the severity of the patient's symptoms, and the particular composition or route of administration selected.
  • An exemplary, non-limiting range for a therapeutically effective amount of a inhibitor of the present invention is about 0.1-100 mg/kg, such as about 0.1-50 mg/kg, for example about 0.1- 20 mg/kg, such as about 0.1-10 mg/kg, for instance about 0.5, about such as 0.3, about 1, about 3 mg/kg, about 5 mg/kg or about 8 mg/kg.
  • An exemplary, non-limiting range for a therapeutically effective amount of a inhibitor of the present invention is 0.02-100 mg/kg, such as about 0.02-30 mg/kg, such as about 0.05-10 mg/kg or 0.1-3 mg/kg, for example about 0.5-2 mg/kg. Administration may e.g.
  • the efficacy of the treatment is monitored during the therapy, e.g. at predefined points in time. In some embodiments, the efficacy may be monitored by visualization of the disease area, or by other diagnostic methods described further herein, e.g. by performing one or more PET-CT scans.
  • an effective daily dose of a pharmaceutical composition may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the human monoclonal antibodies of the present invention are administered by slow continuous infusion over a long period, such as more than 24 hours, in order to minimize any unwanted side effects.
  • An effective dose of a inhibitor of the present invention may also be administered using a weekly, biweekly or triweekly dosing period. The dosing period may be restricted to, e.g., 8 weeks, 12 weeks or until clinical progression has been established.
  • treatment according to the present invention may be provided as a daily dosage of a inhibitor of the present invention in an amount of about 0.1-100 mg/kg, such as 0.2, 0.5, 0.9, 1.0, 1.1,
  • the agent of the present invention is administered to the patient in the form of a pharmaceutical composition which comprises a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, di sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, polyethylene glycol and wool fat.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • the used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • Sterile injectable forms of the compositions of this invention may be aqueous or an oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include, e.g., lactose.
  • the active ingredient is combined with emulsifying and suspending agents.
  • certain sweetening, flavoring or coloring agents may also be added.
  • the compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • Such materials include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • the compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Patches may also be used.
  • the compositions of this invention may also be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • an antibody present in a pharmaceutical composition of this invention can be supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials.
  • the product is formulated for IV administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and Sterile Water for Injection. The pH is adjusted to 6.5.
  • An exemplary suitable dosage range for an antibody in a pharmaceutical composition of this invention may between about 1 mg/m 2 and 500 mg/m 2 .
  • schedules are exemplary and that an optimal schedule and regimen can be adapted taking into account the affinity and tolerability of the particular antibody in the pharmaceutical composition that must be determined in clinical trials.
  • a pharmaceutical composition of the invention for injection e.g., intramuscular, i.v.
  • FIGURES are a diagrammatic representation of FIGURES.
  • FIG. 1 Tumor cell-derived hyaluronic acid (HA) oligomers deplete lipid rafts in macrophages.
  • A BMDM were co-cultured with live or paraformaldehyde-treated (fixed) ID8 cells, prior to CTB staining, quantification of CTCF is shown.
  • B High and low molecular weight fractions of ID8-CM were prepared using Centricon filters with 100 kDa pores, each fraction was compared with unfractionated ID8-CM for effects on CTB staining.
  • C BMDM were treated with ID8-CM with and without hyaluronidase (HAse) treatement prior to CTB staining and quantification.
  • D BMDM were incubated with HA oligomers of increasing molecular weights before CTB staining and quantification, ID8-CM was used as a positive control.
  • (A,B) BMDM were treated with or without ID8-CM before stimulation with increasing concentrations of IL-4 or IFNy for 8 hours.
  • (C) BMDM were treated with different cholesterol depleting agents; 9-cis-retenoic acid (9cRA), high-density lipoprotein (HDL) or apolipoprotein A1 (ApoAl), as well as ID8- CM; lipid raft density was subsequently measured by CTB staining, quantification of CTCF is shown.
  • IL-4 (20 ng/ml) induced Argl and IFNy (20 ng/ml) induced Nos2 expression in BMDM treated with 9cRA, HDL or ApoAl, compared to ID8-CM.
  • E BMDM from Abcal/g and Abcal/gl ALyz2 mice were incubated with ID8-CM, 9cRA, HDL or ApoAl and lipid raft density was measure by CTB staining, quantification of CTCF is shown.
  • F IL-4 induced Argl and IFNy induced Nos 2 expression in BMDM from A bcaJ gjd and A heal gU l vz2 mice with and without ID8-CM treatment.
  • LY294002 Torin, Rapamycin (Merck); hyaluronic acid, hyaluronidase, methyl-P-cyclodextrin, apolipoprotein Al, high-density lipoprotein, 9-cis-retenoic acid and cholesterol-methyl- -cyclodextrin (Sigma); recombinant mouse IL-4, IFNy and M-CSF (Peprotech); IL4Ra neutralizing antibody (eBioscience).
  • C57B1/6 mice were obtained from Charles River. All transgenic mouse strains were backcrossed to a C57B1/6 background.
  • Abcal tmlJp Abcgl tmlTal1 (A heal gl ff ) and Lyz2 tml(cre)I ⁇ ° ( Lyz2 Cre ) mice were obtained from Jackson Laboratories.
  • Slal6 mice were kindly donated by Dr. Bernard Malissen (CIML, Marseille, FR), A heal mice by Prof. Miranda VanEck (Leiden University, NL) and Pik3cct mice by Prof. Martin Turner (Babraham Institute, Cambridge, UK).
  • mice were anaesthetised with Ketamine (150 mg/kg) and Xylazine (10 mg/kg) and placed in 6 mm thick lead cylinders, exposing only the hind legs. With the peritoneal cavity protected, mice were irradiated with 9 Gy and reconstituted with 10 7 bone marrow cells from Ccr2 ⁇ / ⁇ (CD45.2) and CD45.1/2 mice, at a ratio of 4: 1. After 5 weeks, chimerism of blood leukocytes was assessed by flow cytometry.
  • mice All mice were housed under specific pathogen-free conditions and animal experimentation was conducted in strict accordance with good animal practice as defined by the French animal welfare bodies relative to European Convention (EEC Directive 86/609) and approved by the Direction Departmental des Services Veterinaires des Bouches du Rhones.
  • Bone marrow derived macrophages were obtained as previously described (Hagemann et al., 2008); briefly, femurs and tibiae from mice aged 8 to 10 weeks were flushed and cells collected by centrifugation at 450 g for 5 min at 4°C.
  • ID8 cell-conditioned conditioned medium ID8-CM
  • 13.75 xlO 6 cells in 25 ml were incubated for 72 hours in a 175 cm 2 flasks in DMEM containing 4 % of FCS.
  • DMEM fetal calf serum
  • BMDM BMDM were grown in Lab-Tek chambered slides (ThermoFisher Scientific) and fixed with 4 % PFA, permeabilised (0.1 % Triton-X100) and blocked in 5 % BSA with 10 mM glycine.
  • the following primary antibodies were used for incubation during 90 minutes at 4°C; anti-pSTATl, anti-pSTAT6, anti-pSer473-Akt, anti-pThr308-Akt, anti-PHL (Cell Signaling). After washing, anti-rabbit-Alexa488 (Invitrogen) and TO-PRO-3 (ThermoFisher Scientific) were added for 60 minutes.
  • Lipid rafts were stained using the Vybrant Alexa Fluor 488 Lipid Raft Labelling Kit, following manufacturer’s instructions. Briefly, BMDM were grown and stimulated in Lab-Tek chambered slides. After washing with serum- free DMEM, they were incubated for 10 minutes with Alexa488-conjugated cholera toxin subunit B (CTB) at 4°C, followed by cross-linking with an anti-CTB antibody for 15 minutes at 4°C. Subsequently, the cells were fixed with 4 % Antigenfix (DiaPath) for 10 minutes on ice and nuclei were stained with TO-PRO-3. The di-4-ANEPPDHQ lipid raft staining protocol was adapted from the one described by Owen et al.
  • Total cell cholesterol content was measured in BMDM using the Amplex Red Cholesterol Assay kit (ThermoFisher Scientific), according to the manufacturer’s instructions.
  • BMDM were lysed on ice in lysis buffer supplemented with proteinase inhibitor cocktail, PNPP, b-glycerophosphate and DTT. Separation by SDS-PAGE was followed by blotting on PVDF membrane. Blots were blocked with 5 % skimmed milk in TBS- 0.05 %Tween20. The following primary antibodies were used; anti-Nos2, anti-Argl (Santa Cruz), anti-P-Actin (Sigma), anti-Akt and anti-pSer473-Akt (Cell Signaling). Primary antibodies were incubated overnight at 4°C and appropriate HRP-conjugated secondary antibodies (DAKO) for 1 hour at room temperature. Chemoluminescence was detected by Pierce ECL Western Blotting Substrate (Thermo Scientific).
  • One million ID8 cells were injected intraperitoneally in the different mouse strains using a 27G syringe. Mice were euthanised at the indicated times and peritoneal lavages were collected for cytometric analysis, ex vivo bioluminescence measurement and/or lipid raft staining. Briefly, 9 ml of ice cold PBS was injected intraperitoneally and after a careful massage to detach all the cells in the cavity, peritoneal fluid was collected through a 23 G syringe. Tubes were weighed to determine the recovered lavage volume and the cell density was assessed using a Casy cell counter (Innovatis). Cells were centrifugated and resuspended in 1 ml cold PBS.
  • Peritoneal lavage cells underwent a short NFLCl red blood cell lysis and were incubated at 4°C for 10 min with the 2.4.G2 antibody to block Fc receptors. The cells were stained with the indicated antibodies for 30 min at 4°C. Dead cells were gated out using SYTOX Blue dead cell stain (Life Technlogies). After cell-surface staining, cells were fixed. Analysis was performed using an LSR-II flow cytometer or sorted using an Aria III cell sorter (both BD Biosciences) and data analysis was conducted with the FlowJo cytometric analytical software (Tree Star).
  • Anti-CD l ib (Ml/70), anti-CD44 (IM7), anti-CD45.1 (A20), anti-CD45.2 (104), NK1.1, Ly6G, anti-CD5 (53-7.3), anti-CD19 (1D3), anti-CD64, anti-Ly6C (AL-21), anti-F4/80 and anti-MHCII (M5/114) were purchased from BD Biosciences, eBioscience, BioLegend, and Life Technologies.
  • RNA samples were hybridised on Affymetrix Mouse 430 2.0 or MoGene 1.0 st chips. Samples were processed as follows: The biotinylated cRNAs were prepared according to a double amplification protocol using MessageAmpTM II aRNA Amplification Kit (Ambion). The images of the chips were generated with Affymetrix software AGCC version 3.2. The expression data was then extracted with the Affymetrix Expression Console version 1.1 software using the RMA (log2 scale) and MAS5 (linear scale) algorithms. Gene Set Enrichment Analysis (GSEA, Broad Institute) (Subramanian et al, 2005) was used to examine differentially expressed genes (DEGs).
  • GSEA Gene Set Enrichment Analysis
  • GSEA GSEA
  • ES enrichment plot
  • NES normalised enrichment score
  • FDR False Discovery rate
  • HGSC High grade serous ovarian cancer
  • ID8 cells are spontaneously transformed mouse ovarian surface epithelial cells (Urzua et al., 2016), when adoptively transferred by intra-peritoneal (i.p.) injection in syngeneic mice, these cells progressively develop a malignant ascites with tumor nodules throughout the peritoneal cavity (Hagemann et al, 2008), which is characteristic of HGSC.
  • the peritoneal cavity is populated by two major subsets of serosal macrophages; large peritoneal macrophages (LPM), which are most abundant, and a minor population of small peritoneal macrophages (SPM) (Ghosn et al., 2010).
  • LPM large peritoneal macrophages
  • SPM small peritoneal macrophages
  • Previous studies have shown that SPM and LPM have distinct developmental origins; SPM develop from blood monocytes which are derived from bone marrow progenitors, whereas LPM are derived from embryonic progenitors and are maintained independently of blood monocytes, retaining proliferative capacity for self-renewal (Yona et al., 2013).
  • LPM represent approximately 80 % of PM in naive mice, however, after seeding of ID8 cells in the peritoneal cavity, a significant population of F4/80 mt MHCIT nt PM rapidly accumulates (intPM; data not shown).
  • Kinetic analysis of total cell numbers revealed that LPM numbers remain relatively constant throughout tumor progression, while intPM progressively accumulate and eventually become the dominant TAM population (data not shown).
  • Radiation chimeras can be used to determine the contribution of bone marrow-derived progenitors towards cells in a given tissue.
  • irradiation kills tissue-resident macrophages that then become replaced by monocyte- derived cells, thus to distinguish tissue-resident cells from monocyte-derived macrophages from the bone marrow, it is necessary to protect the tissue from the effects of radiation using lead shielding.
  • chemokine receptor Cx3crl is expressed by blood monocytes (Geissmann et ah, 2003) and previous studies have demonstrated the fate-mapping of monocyte-derived cells using knock- in mice that express a tamoxifen-inducible Cre-recombinase from the Cx3crl locus (Cx3crl CreER ), crossed to mice expressing a ubiquitous lox-STOP-lox reporter cassette (Yona et al, 2013).
  • Cx3crl CreER mice with Rosa26-lsl-tdRFP reporter mice (Cx3cr7 CreER :R26-tdRFP) and injected these mice with ID8 cells to track monocyte-derived cells during tumor growth.
  • mice Six weeks after injection of ID8 cells, mice were given a single dose of 4-OHT by oral gavage (p.o.) and RFP expression in TAM subsets was measured by flow cytometry ten days later. These experiments showed strong RFP labelling in SPM and intPM within 10 days of 4-OHT administration, with very little labelling of LPM (data not shown). These data clearly demonstrated the contribution of blood monocytes to SPM and intPM during tumor growth, even within this short time frame.
  • This compiled geneset also showed a significant enrichment in TAM and among the up-regulated genes were known actors in cholesterol metabolism and efflux, including; Abcgl, Ldlr, Pparg, Hmgcsl, Hmgcr, Srebf2 (data not shown).
  • Cholesterol rich membrane micro-domains are commonly measured using cholera toxin B (CTB) staining, which binds to ganglioside GM1, the accumulation of which is linked with membrane cholesterol content.
  • CTB cholera toxin B
  • Tumor cell-derived hyaluronic acid drives cholesterol efflux in macrophages.
  • ID8 cells increased cholesterol efflux from macrophages. This effect could be recapitulated with conditioned medium but not with fixed cells (Fig.1 AT indicating that cholesterol efflux is promoted by a secreted factor.
  • Fig.1 AT indicating that cholesterol efflux is promoted by a secreted factor.
  • ID8-CM we exposed ID8-CM to a series of treatments, including ultra centrifugation, boiling (95°C for 5 min), repeated freeze/thaw cycles, DNAse and proteinase K, none of which had any impact on the ability of ID8-CM to deplete CTB staining in macrophages (data not shown).
  • receptors for HA are expressed by TAM, namely CD44 and Lyve-1 (Chanmee et al., 2016; Turley et al, 2002).
  • TAM hyaluronidase
  • Cholesterol efflux promotes IL-4 mediated macrophage reprogramming.
  • TAM tumor-promoting phenotype that can be driven by Th2 cytokines such as IL-4 or IL-13, and are skewed away from the pro-inflammatory and immunostimulatory activation state, for example induced by Thl cytokines such as IFNy (DeNardo et al, 2009; Murray et al, 2014).
  • ID8 cells To test the effects of ID8 cells on macrophage reprogramming, we stimulated BMDM with IL-4 or IFNy in the presence or absence of ID8-CM and measured the induction of IL-4 and IFNy gene expression, respectively.
  • ID8-CM pre-treatment profoundly increased the expression of IL-4 induced genes; Argl , Retnla , CM313 and Mrcl (Fig.2A).
  • ID8-CM inhibited the IFNy induced expression of Nos2 and III 2b (Fig.2B).
  • ID8-CM promoted macrophage programming towards an IL-4 induced pro-tumor phenotype.
  • IL4RA IL4 receptor alpha chain
  • Tumor-induced macrophage reprogramming is STAT6 and PI3K dependent.
  • IL-4 receptor signaling pathways we analyzed IL-4 receptor signaling pathways.
  • IL4RA IL- 4 receptor
  • IL-4 induced gene expression is regulated by JAK-mediated phosphorylation of the STAT6 transcription factor.
  • IL-4 signaling also activates PI3K, which was recently shown to be an important pathway for the tumor-promoting functions of TAM (Kaneda et al, 2016a; Kaneda et al, 2016b), furthermore, increased PI3K signaling has been shown to promote IL-4 induced gene expression in macrophages (Rauh et al., 2005).
  • PI3K activation we measured phosphorylation of the downstream kinase Akt/PKB.
  • macrophages lacking the ABCAl and ABCGl cholesterol efflux transporters failed to increase pY-STAT6 and pS-Akt upon treatement with ID8-CM (data not shown).
  • increased pY-STAT6 and pS-Akt accumulation was restricted to the high molecular weight (>100 kDa) fraction of ID8-CM and could be reversed by HAse treatment (data not shown), indicating that HA-mediated cholesterol efflux promoted increased STAT6 and Akt activation.
  • rapamycin which blocks mTORCl
  • Torin which blocks both mTORCl and mTORC2.
  • Rapamycin treatment only partially inhibited ID8-CM induced pS-Akt accumulation in macrophages, however, Torin treatment completely inhibited ID8-CM induced pS-Akt phosphorylation in a dose-dependent manner (data not shown), suggesting that mTORC2 activity is required for ID8-CM induced pS-Akt accumulation in macrophages.
  • IL-4 induced macrophage activation or reprogramming in response to ID8- CM requires PI3K-mTORC2-Akt activity and is driven by STAT6.
  • IL-4 induced STAT6 and PI3K signaling in TAM drives tumor progression in EOC.
  • Tim4 was previously shown to be a marker for proliferative, self-renewing LPM (Rosas et al., 2014), whereas Tim4 F4/80 hl cells represent monocyte-derived LPM, which are CCR2-dependent (data not shown).
  • Tim4 F4/80 hl cells represent monocyte-derived LPM, which are CCR2-dependent (data not shown).
  • TAM sorted from these mice showed a significant downregulation of genes associated with the IL-4 dependent TAM phenotype and a positive enrichment for tumoricidal genes (data not shown), reflecting the phenotype of PI3K deficient TAM.
  • TAM tumor-associated macrophages
  • TAM can contribute to tumor progression by various mechanisms, including immune-suppression and trophic functions, supporting angiogenesis, cell proliferation, invasion and metastasis.
  • arginase I Argl
  • Argl arginase I
  • macrophages also possess intrinsic anti-tumor potential, through direct tumoricidal functions and orchestrating anti-tumor immunity, which may be particularly relevant in response to therapy (Bonnotte et al., 2001; Hagemann et al., 2008; Mytar et al., 1999). But the mechanisms by which TAM become polarized towards pro-tumor functions remain poorly understood.
  • TAM epithelial ovarian cancer
  • EOC epithelial ovarian cancer
  • HGSC high-grade serous ovarian cancer
  • LPM large peritoneal macrophages
  • MN-derived macrophages small peritoneal macrophages
  • TAM displayed a more pro- inflammatory gene signature, which strongly distinguished them from naive resident PM.
  • TAM acquired a phenotype more closely resembling resident PM, which suggested a dynamic reprogramming of TAM phenotype during tumor progression.
  • Reverse cholesterol efflux in macrophages is regulated by membrane cholesterol efflux transporters, such as ABCA1 and ABCG1. These transporters regulate the levels of cholesterol in the plasma membrane, which has a profound influence on macrophage responses to extracellular stimuli.
  • ABCA1 deficient macrophages accumulate cholesterol in the membrane and are hyperresponsive to pro-inflammatory stimuli, such as bacterial lipopolysaccharide (LPS) (Fessler and Parks, 2011; Pradel et al, 2009). This is thought to be due to the increase in cholesterol-rich membrane microdomains, also called lipid rafts, which are required to promote TLR4-signaling.
  • pro-inflammatory stimuli such as bacterial lipopolysaccharide (LPS) (Fessler and Parks, 2011; Pradel et al, 2009).
  • LPS bacterial lipopolysaccharide
  • cholesterol-rich membrane microdomains also called lipid rafts, which are required to promote TLR4-signaling.
  • previous studies have also shown that ABCA1 -deficient macrophages are hyporesponsive to other stimuli, including IL-4 and IL-13 (Pradel et al, 2009).
  • ovarian cancer cells actively promoted membrane cholesterol efflux in macrophages, which was associated with increased IL-4 signaling and inhibition of IFNy-induced gene expression, resulting in transcriptional and functional reprogramming of TAM.
  • Depletion of membrane cholesterol in macrophages increased PI3K activity and mTORC2-mediated Akt phosphorylation. Both PI3K and mTORC2 have previously been linked with IL-4 mediated macrophage activation in different contexts (Huang et al., 2016; Rauh et al, 2005).
  • PI3K was recently shown to be a critical pathway to maintain the pro-tumor functions of TAM (Kaneda et al, 2016a; Kaneda et al., 2016b).
  • cholesterol-rich membrane microdomains are required to recruit negative regulators of PI3K activity, such as the lipid phosphatase SHIP-1.
  • SHIP may reside in detergent-resistant membrane fractions (Galandrini et al., 2002) and SHIP-1 is known to inhibit IL-4 signaling in macrophages (Rauh et al., 2005).
  • HA hyaluronic acid
  • HA is a major component of the extracellular matrix (ECM) in many human cancers, including ovarian cancer and in many cases the degree of HA accumulation strongly correlates with poor prognosis (Kolapalli et al., 2016; Sironen et al., 2011). Macrophages express at least two distinct receptors for HA; CD44 and Lyvel . Interestingly, CD44 signaling has previously been associated with PI3K activation in TAM (Lenart et al., 2017).
  • PI3K also upregulates ABCA1 expression in macrophages (Chen et al., 2012; Okoro et al., 2016), potentially creating a feed-forward loop for enhanced cholesterol efflux and IL-4 mediated reprogramming.
  • Hyaluronan A modulator of the tumor microenvironment. Cancer Lett 375, 20-30.
  • TNF-alpha The tumor- promoting actions of TNF-alpha involve TNFR1 and IL-17 in ovarian cancer in mice and humans. J Clin Invest 119, 3011-3023.
  • CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16, 91-102.
  • PBKgamma is a molecular switch that controls immune suppression. Nature 539, 437-442.
  • Hyaluronan carried by tumor-derived microvesicles induces IL-10 production in classical (CD14(++)CD16(-)) monocytes via PI3K/Akt/mTOR-dependent signalling pathway.
  • BiNGO a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 21, 3448-3449.
  • CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222-225.
  • the transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal. Science 344, 645-648.
  • Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun 7, 10321.
  • BubbleGUM automatic extraction of phenotype molecular signatures and comprehensive visualization of multiple Gene Set Enrichment Analyses. BMC Genomics 16, 814.

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Abstract

Il a été montré que les macrophages associés aux tumeurs (TAM) jouent des rôles importants dans la progression maligne de divers cancers. Cependant, les macrophages possèdent également une activité tumoricide intrinsèque et peuvent favoriser l'activité de lymphocytes cytotoxiques, mais ils adoptent rapidement un phénotype alternatif au sein des tumeurs, associé à des fonctions de suppression immunitaire et trophiques qui soutiennent la croissance tumorale. Les mécanismes qui favorisent la polarisation des TAM dans le micro-environnement tumoral restent mal compris, ces mécanismes peuvent représenter des cibles thérapeutiques importantes pour bloquer les fonctions de stimulation tumorale des TAM et rétablir leur potentiel anti-tumoral. Les inventeurs ont ici caractérisé des TAM dans un modèle murin de cancer de l'ovaire métastatique. Ils montrent que les cellules du cancer de l'ovaire favorisent l'efflux de cholestérol membranaire et l'épuisement des radeaux lipidiques des macrophages. L'augmentation de l'efflux de cholestérol favorise la reprogrammation médiée par IL-4 tout en inhibant l'expression génique induite par IFN-. Ces études révèlent un rôle inattendu pour un efflux de cholestérol membranaire induit par une tumeur dans la conduite de la signalisation d'IL-4 et des fonctions de promotion de tumeur des TAM, tout en les rendant réfractaires à des stimuli pro-inflammatoires. Ainsi, la prévention de l'efflux de cholestérol dans des TAM pourrait représenter une nouvelle stratégie thérapeutique pour bloquer des fonctions pro-tumorales et restaurer l'immunité antitumorale.
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