CN116585478A - Brd7联合全反式维甲酸和pd-l1抗体在制备治疗鼻咽癌制剂中的应用 - Google Patents
Brd7联合全反式维甲酸和pd-l1抗体在制备治疗鼻咽癌制剂中的应用 Download PDFInfo
- Publication number
- CN116585478A CN116585478A CN202310377576.9A CN202310377576A CN116585478A CN 116585478 A CN116585478 A CN 116585478A CN 202310377576 A CN202310377576 A CN 202310377576A CN 116585478 A CN116585478 A CN 116585478A
- Authority
- CN
- China
- Prior art keywords
- brd7
- nasopharyngeal carcinoma
- cells
- antibody
- retinoic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 title claims abstract description 104
- 206010061306 Nasopharyngeal cancer Diseases 0.000 title claims abstract description 100
- 201000011216 nasopharynx carcinoma Diseases 0.000 title claims abstract description 100
- 102100029897 Bromodomain-containing protein 7 Human genes 0.000 title claims abstract description 99
- 101000794019 Homo sapiens Bromodomain-containing protein 7 Proteins 0.000 title claims abstract description 97
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 title claims abstract description 52
- 229930002330 retinoic acid Natural products 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 108010074708 B7-H1 Antigen Proteins 0.000 title claims abstract 20
- 102000008096 B7-H1 Antigen Human genes 0.000 title claims abstract 20
- 230000014509 gene expression Effects 0.000 claims abstract description 42
- 230000035755 proliferation Effects 0.000 claims abstract description 8
- 230000017188 evasion or tolerance of host immune response Effects 0.000 claims description 10
- 108090000623 proteins and genes Proteins 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 102000004169 proteins and genes Human genes 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 7
- 101150047363 BRD7 gene Proteins 0.000 claims description 5
- 238000013518 transcription Methods 0.000 claims description 5
- 230000035897 transcription Effects 0.000 claims description 5
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 238000003745 diagnosis Methods 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 72
- 210000001744 T-lymphocyte Anatomy 0.000 abstract description 52
- 230000002018 overexpression Effects 0.000 abstract description 16
- 230000002147 killing effect Effects 0.000 abstract description 10
- 229960003852 atezolizumab Drugs 0.000 abstract description 6
- 230000001506 immunosuppresive effect Effects 0.000 abstract description 3
- 230000025084 cell cycle arrest Effects 0.000 abstract description 2
- 230000003993 interaction Effects 0.000 abstract description 2
- 210000004881 tumor cell Anatomy 0.000 description 16
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 12
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 12
- 238000003501 co-culture Methods 0.000 description 12
- 238000001514 detection method Methods 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 9
- 238000012258 culturing Methods 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 239000013612 plasmid Substances 0.000 description 9
- 210000000981 epithelium Anatomy 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 238000001262 western blot Methods 0.000 description 7
- 230000006907 apoptotic process Effects 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 238000009169 immunotherapy Methods 0.000 description 6
- 230000002452 interceptive effect Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- 102100037850 Interferon gamma Human genes 0.000 description 4
- 108010074328 Interferon-gamma Proteins 0.000 description 4
- 238000011529 RT qPCR Methods 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 238000010166 immunofluorescence Methods 0.000 description 3
- 238000013115 immunohistochemical detection Methods 0.000 description 3
- 238000011532 immunohistochemical staining Methods 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000007619 statistical method Methods 0.000 description 3
- 238000011729 BALB/c nude mouse Methods 0.000 description 2
- 101710126818 Bromodomain-containing protein 7 Proteins 0.000 description 2
- 108010077544 Chromatin Proteins 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 230000006052 T cell proliferation Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 210000003483 chromatin Anatomy 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 238000003235 crystal violet staining Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 2
- 238000007634 remodeling Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000005740 tumor formation Effects 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 108091005575 Bromodomain-containing proteins Proteins 0.000 description 1
- 102000001805 Bromodomains Human genes 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000033540 T cell apoptotic process Effects 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000002659 cell therapy Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000009643 clonogenic assay Methods 0.000 description 1
- 231100000096 clonogenic assay Toxicity 0.000 description 1
- 230000005757 colony formation Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 238000011502 immune monitoring Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000003125 immunofluorescent labeling Methods 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 230000010304 tumor cell viability Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 150000002266 vitamin A derivatives Chemical class 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/5748—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving oncogenic proteins
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Analytical Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Pathology (AREA)
- Oncology (AREA)
- Microbiology (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Physics & Mathematics (AREA)
- Biotechnology (AREA)
- Hospice & Palliative Care (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Physics & Mathematics (AREA)
- Food Science & Technology (AREA)
- Zoology (AREA)
- Cell Biology (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Mycology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Abstract
本发明公开了BRD7联合全反式维甲酸和PD‑L1抗体在制备治疗鼻咽癌制剂中的应用。在前期研究中发现过表达BRD7能够抑制PD‑L1的表达,抑制鼻咽癌细胞的增殖;全反式维甲酸(ATRA)能够显著抑制鼻咽癌细胞的增殖,并诱导其发生细胞周期停滞;PD‑L1抗体(Atezolizumab)可以阻断免疫抑制检查点PD‑1/PD‑L1之间的相互作用,使T细胞重新活化并增强对鼻咽癌细胞的杀伤作用。过表达BRD7、全反式维甲酸、PD‑L1抗体三者的联合使用为鼻咽癌患者带来了福音。
Description
技术领域
本发明属于鼻咽癌免疫治疗技术领域,具体涉及BRD7联合全反式维甲酸和PD-L1抗体在制备治疗鼻咽癌制剂中的应用。
背景技术
鼻咽癌(nasopharyngeal carcinoma,NPC)是高发于我国南方地区的一种来源于鼻咽黏膜的头颈部恶性肿瘤,由EB病毒感染、遗传、环境等多种因素所致,具有发病隐匿、恶性程度高、易发生侵袭迁移、有明显的地域及家族聚集性等特点。因此,鼻咽癌的治疗难度较大。目前,鼻咽癌治疗遵循“放疗为主,化疗为辅,特殊情况下选择手术”的总体原则,对于局部晚期或复发鼻咽癌患者,可联合应用分子靶向及免疫治疗等新型生物治疗手段。近年来鼻咽癌的免疫治疗发展迅速,取得了一些研究成果,并且其可以在不破坏机体免疫系统结构和功能的前提下发挥抗肿瘤作用,进而改善患者的生活质量,并最终延长患者生命。
含溴域蛋白7(bromodomain-containing protein 7,BRD7)是含溴域蛋白家族的成员,又称Celtix-1,是由BRD7基因编码的SWI/SNF染色质重塑复合物的PBAF形式的组分之一。我们研究中发现在鼻咽癌活检和细胞系中发现BRD7表达水平降低,而后作为一个鼻咽癌候选抑瘤基因和核转录因子作用被证实,即BRD7主要定位在细胞核,能够调节染色质重塑、阻滞细胞周期进展、促进细胞凋亡、逆转鼻咽癌细胞恶性表型。但目前BRD7与鼻咽癌免疫治疗之间的关系尚未有研究。
全反式维甲酸(All-trans retinoic acid,ATRA)是维生素A的代谢中间物,通过其核受体以转录因子样的方式在免疫和胚胎发育等各种生物过程中发挥重要作用。我们研究表明,ATRA显着抑制鼻咽癌细胞生长并诱导细胞周期停滞。ATRA可诱导未成熟的髓系细胞分化为成熟的血细胞,也可激活CD8+T细胞的抗肿瘤作用,因此ATRA可能作为鼻咽癌潜在的免疫治疗药物。但ATRA与BRD7之间及其与鼻咽癌细胞免疫逃逸的关系尚未见报道。
在鼻咽癌中,PD-L1表达的上调能通过PD-1/PD-L1轴使肿瘤浸润性T淋巴细胞功能减弱,抑制T细胞活化,有助于肿瘤细胞逃避免疫监视,促进肿瘤细胞的生长增殖。阿替利珠单抗(Atezolizumab)是一种人源化单克隆抗体,作为程序性细胞死亡配体(PD-L1)阻断剂,于2016年获得美国食品药品监督管理局FDA批准上市。阿替利珠单抗能与肿瘤细胞上的PD-L1结合,并阻断其与T细胞及抗原递呈细胞PD-1的相互作用,从而解除PD-1介导的免疫抑制,促进T细胞攻击肿瘤细胞。目前研究表明以抗PD-1/PD-L1治疗为代表的免疫治疗对鼻咽癌显示出有效性,但是PD-1/PD-L1阻断治疗的有效率只有20%-30%,因此将抗PD-1/PD-L1疗法与其他方法联用以增强免疫治疗的效果成为一种可行的策略与方法。
鉴于此,特提出本发明。
发明内容
本发明的第一个方面的目的是提供全反式维甲酸和PD-L1抗体或者BRD7和PD-L1抗体在制备治疗鼻咽癌制剂中的应用。
本发明的第二个方面的目的是提供一种治疗鼻咽癌制剂,包括全反式维甲酸和PD-L1抗体或者BRD7和PD-L1抗体。
本发明的第三个方面的目的是提供BRD7联合全反式维甲酸和PD-L1抗体在制备治疗鼻咽癌制剂中的应用。
进一步地,所述的BRD7包括BRD7基因表达产物或者过表达BRD7的试剂。
本发明的第四个方面的目的是提供一种治疗鼻咽癌制剂,包括BRD7、全反式维甲酸和PD-L1抗体。
进一步地,所述的BRD7包括BRD7基因表达产物或者过表达BRD7的试剂。
经发明人实验验证发现,在鼻咽癌细胞中过表达或干扰BRD7的表达能够分别显著抑制或增加细胞中PD-L1的表达。
经发明人实验验证发现,全反式维甲酸(ATRA)处理会使鼻咽癌细胞中BRD7表达增加,PD-L1表达降低。
本发明的第五个方面的目的是提供全反式维甲酸和PD-L1抗体或者BRD7和PD-L1抗体在制备抑制鼻咽癌细胞增殖和免疫逃逸的药物中的应用。
本发明的第六个方面的目的是提供BRD7联合全反式维甲酸和PD-L1抗体在制备抑制鼻咽癌细胞增殖和免疫逃逸的药物中的应用。
本发明的第七个方面的目的是提供全反式维甲酸和PD-L1抗体或者BRD7和PD-L1抗体在制备抑制人鼻咽癌细胞的CD274转录水平和蛋白水平,进而降低鼻咽癌细胞表面PD-L1表达的药物中应用。
本发明的第八个方面的目的是提供BRD7联合全反式维甲酸和PD-L1抗体在制备抑制人鼻咽癌细胞的CD274转录水平和蛋白水平,进而降低鼻咽癌细胞表面PD-L1表达的药物中应用。
本发明的第九个方面的目的是提供检测BRD7表达水平的试剂在制备鼻咽癌诊断制剂中的应用。
在本发明应用较佳的实施方式中,上述全反式维甲酸(ATRA)为维生素A的一种代谢衍生物,PD-L1抗体为PD-L1的选择性人源化单克隆IgG1抗体Atezolizumab(源自Proteintech,1㎎/支)。
本发明首次发现,在鼻咽癌细胞中过表达BRD7,能够抑制PD-L1的表达,抑制鼻咽癌细胞的增殖;ATRA能够提高细胞中BRD7的表达,抑制鼻咽癌细胞中PD-L1的表达,并且BRD7与全反式维甲酸和PD-L1抗体联合使用可以使鼻咽癌细胞表面PD-L1表达减低,T淋巴细胞表面PD-1表达降低,增强CD8+T淋巴细胞对鼻咽癌细胞的杀伤效果,显著抑制鼻咽癌细胞的生长,促进过继性T细胞疗法的治疗效果。因此BRD7与全反式维甲酸和PD-L1抗体的联合应用可以实现治疗鼻咽癌细胞的免疫逃逸,三者的联用为鼻咽癌患者的免疫治疗提供了新的思路与策略。
经发明人实验验证发现,Atezolizumab可以作为PD-L1抗体与BRD7和全反式维甲酸联合应用显著提高T细胞对肿瘤细胞的杀伤效果,抑制鼻咽癌细胞的生长。
但需要说明的是,本发明中的PD-L1抗体不限于Atezolizumab,本领域技术人员在本发明公开的内容基础上,容易想到使用其他的PD-L1抗体与BRD7和全反式维甲酸联合应用治疗鼻咽癌免疫逃逸,其也是属于本发明的保护范围。
本发明具有以下有益效果:
本发明提供了以BRD7为靶点联合全反式维甲酸和PD-L1抗体治疗鼻咽癌免疫逃逸的方法,BRD7过表达与全反式维甲酸和PD-L1抗体联合应用,可以增强T细胞对鼻咽癌细胞的杀伤能力,抑制鼻咽癌细胞免疫逃逸,即BRD7基因联合全反式维甲酸和PD-L1抗体治疗鼻咽癌细胞免疫逃逸可以作为鼻咽癌免疫治疗的新方法、新策略。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,应当理解,以下附图仅展示出了本发明的某些实施例,因此不应被看作是对范围的限定,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他相关的附图。
图1对临床病人进行随访并对OS(总生存期)和DFS(无病生存期)进行统计分析。
图2为临床鼻咽癌组织(NPC)及正常鼻咽上皮组织(NT)中BRD7免疫组化检测图。
图3为临床鼻咽癌组织(NPC)及正常鼻咽上皮组织(NT)中PD-L1免疫组化检测图。
图4为在临床鼻咽癌组织及正常鼻咽上皮组织中进行BRD7与PD-L1的免疫组化检测后,进行评分并作统计分析图。
图5为临床鼻咽癌组织及正常鼻咽上皮组织中,BRD7与PD-L1多重免疫荧光组化检测图。上图为NT组,下图为NPC组,其中绿色荧光代表BRD7,红色荧光代表PD-L1,能够看出二者表达成负相关。
图6为qRT-PCR检测鼻咽癌细胞中BRD7与PD-L1的mRNA水平。
图7为Western Blot检测鼻咽癌细胞中BRD7与PD-L1的蛋白表达水平。
图8为免疫荧光检测鼻咽癌细胞中BRD7与PD-L1表达。
图9全反式维甲酸处理鼻咽癌细胞后Western Blot检测BRD7、PD-L1表达水平变化。
图10为鼻咽癌细胞与T细胞共培养24h后对下层肿瘤细胞进行cck8实验检测细胞活力。
图11为鼻咽癌细胞与T细胞共培养24小时后继续培养7天,对下层肿瘤细胞进行结晶紫染色。
图12为过表达或干扰BRD7后的鼻咽癌细胞与T细胞共培养6h后,收集上清中T细胞,通过流式分析T细胞PD-1表达情况及T细胞凋亡情况。
图13为过表达或干扰BRD7后的鼻咽癌细胞与T细胞,PD-L1抗体共培养6h后,收集上清中T细胞,通过流式分析T细胞PD-1表达情况及T细胞凋亡情况。
图14为过表达或干扰BRD7后的鼻咽癌细胞与T细胞,PD-L1抗体共培养6h后,收集上清中T细胞,通过ELISA测定上清中IFN-γ的含量。
图15为在雌性BALB/c裸鼠体内进行皮下成瘤,并通过尾静脉注射T淋巴细胞模拟体内微环境,注射PD-L1抗体和ATRA处理后体内成瘤情况。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1
本实施例证明,BRD7低表达提示鼻咽癌患者预后不良(图1)。(BRD7引物序列为:5′-agccaggctactgccctg-3';5′-ggagtccaaacgccctggt-3′;基因序列:ATGGGCAAGAAGCACAAGAAGCACAAGTCGGACAAACACCTCTACGAGGAGTATGTAGAGAAGCCCTTGAAGCTGGTCCTCAAAGTAGGAGGGAACGAAGTCACCGAACTCTCCACGGGCAGCTCGGGGCACGACTCCAGCCTCTTCGAAGACAAAAACGATCATGACAAACACAAGGACAGAAAGCGGAAAAAGAGAAAGAAAGGAGAGAAGCAGATTCCAGGGGAAGAAAAGGGGAGAAAACGGAGAAGAGTTAAGGAGGATAAAAAGAAGCGAGATCGAGACCGGGTGGAGAATGAGGCAGAAAAAGATCTCCAGTGTCACGCCCCTGTGAGATTAGACTTGCCTCCTGAGAAGCCTCTCACAAGCTCTTTAGCCAAACAAGAAGAAGTAGAACAGACACCCCTTCAAGAAGCTTTGAATCAACTGATGAGACAATTGCAGAGAAAAGATCCAAGTGCTTTCTTTTCATTTCCTGTGACTGATTTTATTGCTCCTGGCTACTCCATGATCATTAAACACCCAATGGATTTTAGTACCATGAAAGAAAAGATCAAGAACAATGACTATCAGTCCATAGAAGAACTAAAGGATAACTTCAAACTAATGTGTACTAATGCCATGATTTACAATAAACCAGAGACCATTTATTATAAAGCTGCAAAGAAGCTGTTGCACTCAGGAATGAAAATTCTTAGCCAGGAAAGAATTCAGAGCCTGAAGCAGAGCATAGACTTCATGGCTGACTTGCAGAAAACTCGAAAGCAGAAAGATGGAACAGACACCTCACAGAGTGGGGAGGACGGAGGCTGCTGGCAGAGAGAGAGAGAGGACTCTGGAGATGCCGAAGCACACGCCTTCAAGAGTCCCAGCAAAGAAAATAAAAAGAAAGACAAAGATATGCTTGAAGATAAGTTTAAAAGCAATAATTTAGAGAGAGAGCAGGAGCAGCTTGACCGCATCGTGAAGGAATCTGGAGGAAAGCTGACCAGGCGGCTTGTGAACAGTCAGTGCGAATTTGAAAGAAGAAAACCAGATGGAACAACGACGTTGGGACTTCTCCATCCTGTGGATCCCATTGTAGGAGAGCCAGGCTACTGCCCTGTGAGACTGGGAATGACAACTGGAAGACTTCAGTCTGGAGTGAATACTTTGCAGGGGTTCAAAGAGGATAAAAGGAACAAAGTCACTCCAGTGTTATATTTGAATTATGGGCCCTACAGTTCTTATGCACCGCATTATGACTCCACATTTGCAAATATCAGCAAGGATGATTCTGATTTAATCTATTCAACCTATGGGGAAGACTCTGATCTTCCAAGTGATTTCAGCATCCATGAGTTTTTGGCCACGTGCCAAGATTATCCGTATGTCATGGCAGATAGTTTACTGGATGTTTTAACAAAAGGAGGGCATTCCAGGACCCTACAAGAGATGGAGATGTCATTGCCTGAAGATGAAGGCCATACTAGGACACTTGACACAGCAAAAGAAATGGAGATTACAGAAGTAGAGCCACCAGGGCGTTTGGACTCCAGTACTCAAGACAGGCTCATAGCGCTGAAAGCAGTAACAAATTTTGGCGTTCCAGTTGAAGTTTTTGACTCTGAAGAAGCTGAAATATTCCAGAAGAAACTTGATGAGACCACCAGATTGCTCAGGGAACTCCAGGAAGCCCAGAATGAACGTTTGAGCACCAGACCCCCTCCGAACATGATCTGTCTCTTGGGTCCCTCATACAGAGAAATGCATCTTGCTGAACAAGTGACCAATAATCTTAAAGAACTTGCACAGCAAGTAACTCCAGGTGATATCGTAAGCACGTATGGAGTTCGAAAAGCAATGGGGATTTCCATTCCTTCCCCCGTCATGGAAAACAACTTTGTGGATTTGACAGAAGACACTGAAGAACCTAAAAAGACGGATGTTGCTGAGTGTGGACCTGGTGGAAGTTGA)
实施例2
本实施例证明,在鼻咽癌组织中BRD7与PD-L1表达呈负相关。
1.对临床10例正常鼻咽上皮组织以及20例鼻咽癌组织进行免疫组化染色。
免疫组化染色结果显示,BRD7在正常鼻咽上皮组织高表达,在鼻咽癌组织中低表达(图2)。PD-L1在正常鼻咽上皮组织低表达,在鼻咽癌组织中高表达(图3)。对所做免疫组化结果进行统计学分析发现,BRD7与PD-L1(CD274)存在明显的负相关(图4)。
2.通过多重荧光免疫组化检测正常鼻咽上皮组织和鼻咽癌组织中BRD7与PD-L1的表达。
多重荧光免疫组化染色结果证明,BRD7与PD-L1表达存在负相关(图5)。
实施例3
本实施例证明鼻咽癌5-8F细胞和CNE2细胞中BRD7过表达后PD-L1表达显著降低。
1.构建稳定转染BRD7过表达/干扰及对照质粒(BRD7过表达质粒购于优宝生物)的鼻咽癌细胞。5-8F和CNE2细胞均源自中南大学肿瘤研究所。
将生长状态良好的5-8F和CNE2鼻咽癌细胞系消化后铺入六孔板。并以十字方向缓慢晃动,使细胞均匀分布,随后将六孔板放入CO2培养箱,6-8h后待孔内细胞密度达到70%,进行转染。在转染前对细胞进行换液,并配制转染复合物,向100μl无血清DMEM中加入2μg对应质粒和2μlneofect转染试剂,轻柔混匀后室温静置15-20min后加入对应六孔板中,培养24h后换液可继续培养或进行后续实验。
2.通过qRT-PCR证实过表达BRD7可以降低鼻咽癌细胞PD-L1的mRNA水平,干扰BRD7则相反。
在5-8F和CNE2细胞中转染过表达/干扰BRD7质粒及对照质粒后,收集细胞并提取总RNA,逆转录后进行qRT-PCR。qRT-PCR结果显示,在5-8F和CNE2细胞中,与对照组相比,过表达BRD7后PD-L1的mRNA水平降低,干扰BRD7后PD-L1的mRNA水平升高(图6)。
3.通过Western blot证明过表达BRD7可以抑制鼻咽癌细胞中PD-L1表达,干扰BRD7则相反。
在5-8F和CNE2细胞中转染过表达/干扰BRD7质粒及对照质粒后,收集细胞并裂解细胞提取总蛋白进行Western blot检测。Western blot结果显示,在5-8F和CNE2细胞中,与对照组相比,过表达BRD7后PD-L1的蛋白质表达水平降低,干扰BRD7后PD-L1的蛋白质表达水平升高(图7)。
4.采用免疫荧光实验证实过表达BRD7可以抑制鼻咽癌细胞表达PD-L1,干扰BRD7则相反。
将细胞接种到预先放置有盖玻片的六孔板中,待细胞融合成单层细胞后取出盖玻片进行免疫荧光染色,免疫荧光结果证实,与对照组相比,BRD7过表达,红色荧光减弱,干扰BRD7时,红色荧光增强,从而证明BRD7可以抑制鼻咽癌细胞中PD-L1的表达(图8)。
实施例4
本实施例证实,ATRA通过上调BRD7表达进而抑制了PD-L1的表达。
将5-8F和CNE2细胞接种到6孔板中,并用10μM ATRA处理鼻咽癌细胞。加ATRA培养24小时后,收集鼻咽癌细胞,提取总蛋白,进行Western blot检测。通过western blot证明在鼻咽癌细胞中ATRA可以上调BRD7表达,抑制PD-L1表达(图9)。
实施例5
本实施例证明,在鼻咽癌细胞与T细胞共培养时,过表达BRD7与PD-L1抗体联用有助于提高T细胞对肿瘤细胞的杀伤能力。
1.获取外周血单个核细胞并刺激T细胞增殖。
抽取健康成年人外周血并使用Ficoll分离液分离外周血单个核细胞,并将其加入到含有10%FBS和1%双抗1640完全培养基中。活化淋巴细胞,提取出的淋巴细胞添加TCell TransActTM(美天旎,130-128-758)刺激T细胞增殖,期间补充IL-2(20ng/ml)维持淋巴细胞活性。
2.肿瘤细胞-T细胞共培养体系
之前结果已经证明BRD7可以抑制PD-L1的表达,进一步想探索过表达/干扰BRD7后与免疫抑制之间的关系。通过体外构建一个共培养体系模拟免疫微环境,观察在鼻咽癌细胞中过表达/干扰BRD7是否能够影响T细胞的功能。取对数生长期的对照组和过表达/干扰BRD7的5-8F和CNE2细胞在24孔板和96孔板中进行铺板,将人外周血分离的T淋巴细胞与肿瘤细胞按照10:1的比例共培养。同时做两组,在其中一组加入5μg/ml的PD-L1抗体(Atezolizumab)。
3.通过CCK-8实验检测与T细胞共培养后的鼻咽癌细胞活力。
共培养24h后,通过CCK-8检测发现,过表达BRD7后肿瘤细胞活力降低,干扰BRD7后升高。(图10)。
4.通过克隆形成实验检测T细胞对共培养的肿瘤细胞的杀伤能力。
将肿瘤细胞铺至24孔板中培养7天,待形成细胞克隆团后,向其中按照1:10的比例加入T淋巴细胞,共培养24h后,对下层肿瘤细胞进行结晶紫染色。克隆形成实验结果显示,过表达BRD7后T细胞对共培养的肿瘤细胞的杀伤能力升高,干扰BRD7后降低。(图11)。
5.流式细胞术检测T淋巴细胞的凋亡情况及PD-1+CD8+T细胞比例变化。
共培养6h后,收集上清中的T细胞进行流式细胞术检测。流式细胞术结果显示,T细胞与过表达BRD7的鼻咽癌细胞共培养后T细胞凋亡减少,PD-1+CD8+T细胞比例降低。T细胞与干扰BRD7的鼻咽癌细胞共培养后T细胞凋亡增加、PD-1+CD8+T细胞的比例增加,见图12。进一步通过在共培养体系中添加PD-L1抗体,发现过表达BRD7与PD-L1抗体联合使用,进一步阻断鼻咽癌细胞表面PD-L1与T细胞表面PD-1结合,使T细胞凋亡程度更低,PD-1+CD8+T细胞进一步降低(图13)。
6.ELISA检测共培养后T淋巴细胞的IFN-γ分泌情况。
共培养6h后,收集上清进行IFN-γ检测。ELISA结果显示,T细胞与过表达BRD7的鼻咽癌细胞共培养后,T细胞分泌的IFN-γ含量增加。T细胞与干扰BRD7的鼻咽癌细胞共培养后T细胞分泌的IFN-γ含量减少。进一步通过在共培养体系中添加PD-L1抗体,发现过表达BRD7与PD-L1抗体联合使用,进一步促进T淋巴细胞分泌IFN-γ,提高对肿瘤细胞的杀伤能力。(图14)
实施例6
本实施例证明,在雌性BALB/C裸鼠体内进行皮下成瘤时,过表达BRD7与PD-L1抗体和ATRA的联用有助于提高T细胞对肿瘤细胞的杀伤能力,抑制肿瘤的生长。
1.裸鼠皮下成瘤模型的构建
向CNE2细胞中转染BRD7过表达及其对照质粒,将40只小鼠平均分成两组,分别在皮下注射5×106个已转染BRD7过表达或对照质粒的CNE2细胞,将每组进一步分为以下四组:不加T细胞组,T细胞处理组,T细胞/PD-L1抗体处理组,T细胞/PD-L1抗体/ATRA处理组,小鼠皮下所成瘤的任一维度不能超过1.5㎜,当有瘤体即将到达临界值时可将小鼠进行颈椎脱臼处死,并取出瘤组织进行后续实验。
2.体内肿瘤的生长情况
将瘤组织取出后,由图可以看出过表达BRD7,PD-L1抗体处理都能够在一定程度上抑制肿瘤的生长,而过表达BRD7,PD-L1抗体及ATRA三者的联合使用能够最大程度的抑制体内肿瘤的生长。(图15)
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.全反式维甲酸和PD-L1抗体或者BRD7和PD-L1抗体在制备治疗鼻咽癌制剂中的应用。
2.一种治疗鼻咽癌制剂,其特征在于,包括全反式维甲酸和PD-L1抗体或者BRD7和PD-L1抗体。
3.BRD7联合全反式维甲酸和PD-L1抗体在制备治疗鼻咽癌制剂中的应用。
4.根据权利要求3所述的应用,其特征在于,所述的BRD7包括BRD7基因表达产物或者过表达BRD7的试剂。
5.一种治疗鼻咽癌制剂,其特征在于,包括BRD7、全反式维甲酸和PD-L1抗体。
6.全反式维甲酸和PD-L1抗体或者BRD7和PD-L1抗体在制备抑制鼻咽癌细胞增殖和免疫逃逸的药物中的应用。
7.BRD7联合全反式维甲酸和PD-L1抗体在制备抑制鼻咽癌细胞增殖和免疫逃逸的药物中的应用。
8.全反式维甲酸和PD-L1抗体或者BRD7和PD-L1抗体在制备抑制人鼻咽癌细胞的CD274转录水平和蛋白水平,进而降低鼻咽癌细胞表面PD-L1表达的药物中应用。
9.BRD7联合全反式维甲酸和PD-L1抗体在制备抑制人鼻咽癌细胞的CD274转录水平和蛋白水平,进而降低鼻咽癌细胞表面PD-L1表达的药物中应用。
10.检测BRD7表达水平的试剂在制备鼻咽癌诊断制剂中的应用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310288957X | 2023-03-23 | ||
CN202310288957 | 2023-03-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116585478A true CN116585478A (zh) | 2023-08-15 |
Family
ID=87598062
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310377576.9A Pending CN116585478A (zh) | 2023-03-23 | 2023-04-11 | Brd7联合全反式维甲酸和pd-l1抗体在制备治疗鼻咽癌制剂中的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116585478A (zh) |
-
2023
- 2023-04-11 CN CN202310377576.9A patent/CN116585478A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7432624B2 (ja) | Nad+及び/又はnad+阻害剤及び/又はnad+アゴニストの使用及びその配合剤 | |
JP7235259B2 (ja) | Gvhd又は腫瘍を治療するための骨髄系由来サプレッサー細胞のインフラマソーム活性化の調節 | |
CN112426526A (zh) | 一种nk细胞的制备方法及其在治疗癌症中的应用 | |
KR102423631B1 (ko) | 케모카인 억제제, 콜로니 자극 인자 억제제 및 면역항암제를 포함하는 암의 예방 또는 치료용 조성물 및 병용 요법 | |
CN106222141A (zh) | Nk细胞培养液和细胞培养方法 | |
JP2017520582A (ja) | 関節リウマチ治療のための間葉系間質細胞 | |
CN114250198A (zh) | 一种增强免疫细胞抗肿瘤效果的方法 | |
CN104524560A (zh) | 树突状细胞肿瘤疫苗及其制备方法和用途 | |
CN111298111A (zh) | 一种治疗和/或预防癌症的药物和应用 | |
CN116585478A (zh) | Brd7联合全反式维甲酸和pd-l1抗体在制备治疗鼻咽癌制剂中的应用 | |
CN110917347A (zh) | PPARδ拮抗剂联合PD-1抗体在制备肿瘤免疫药物中的应用 | |
CN112138163B (zh) | PPARG激活子联合SIRPα抗体在制备肿瘤免疫药物中的应用 | |
CN109432116A (zh) | 黄芪皂苷ⅲ在制备肿瘤免疫治疗药物中的用途 | |
CN114887080B (zh) | 一种mRNA剂型的免疫抑制剂及其在制备肿瘤治疗药物中的应用 | |
CN116063556B (zh) | Ips来源的car-nk细胞及其治疗癌症的用途 | |
CN115433713B (zh) | 一种自体肿瘤引流淋巴结淋巴细胞的制备方法及其应用 | |
CN116121194B (zh) | 一种肺癌免疫治疗耐药细胞系及其制备方法和应用 | |
CN117625794B (zh) | 一种与食管癌相关的tRF、试剂盒、药物及其应用 | |
CN117462534A (zh) | 川陈皮素在制备抑制pd-l1表达的药物中的应用 | |
CN116999551A (zh) | Plk3的结合/抑制剂及其应用 | |
Lv et al. | Lycium barbarum polysaccharide reduces lung cancer immunotherapy-related endocrine adverse reactions and improves prognosis via interleukin-2 | |
Mccreery et al. | Monocytes and Macrophages in the Cancer Immunity Cycle | |
CN117247466A (zh) | 抗磷脂酰肌醇蛋白聚糖3的嵌合抗原受体及其用途 | |
Liu et al. | IL-37 inhibits glycolysis of lung adenocarcinoma by inhibiting the expression of PFKFB3 | |
CN117018205A (zh) | 基因工程菌sgn1与免疫检查点抑制剂联用在肿瘤治疗中的应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |