CN110687283B - Use of autoantibodies in the diagnosis and/or treatment of tumors - Google Patents
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Abstract
The invention provides application of a reagent for detecting autoantibodies in preparation of products for diagnosing, treating and/or prognosis evaluating tumors and autoimmune diseases, and a marker for diagnosing, treating and/or prognosis evaluating tumors or autoimmune diseases, wherein the marker is an autoantibody. The expression level of the marker is detected by a rapid double-antibody sandwich enzyme-linked immunosorbent assay (rapid-ELISA), and the curative effect response and long-term benefit of the patient to tumor immunotherapy are judged or assisted to be judged.
Description
Technical Field
The invention relates to the field of biomedical detection, in particular to application of an autoantibody in diagnosis, treatment and prognosis evaluation of tumor or autoimmune diseases, wherein the autoantibody is selected from one or more than two of CPLX2, DDX49, PHACTR1, FATE1, UBILD 1, EIF4E2, CCDC130, LPCAT4 or VMAC.
Background
Worldwide health organization global disease burden studies show that cancer is a high mortality disease that is second only to cardiovascular disease worldwide and china. Immunotherapy has become an emerging means of cancer treatment by enhancing the patient's immune system to combat the disease. In many immunotherapeutic strategies, immune checkpoint inhibitors (Immune Checkpoint Blockade, ICB) have shown significant benefits in the treatment of a variety of cancers by blocking the endogenous down-regulation programs of immunity, such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or its ligand (PD-L1). The advent of ICB has increased the overall survival rate of many cancer patients, and many inhibitor drugs are currently approved by the U.S. food and drug administration and the chinese food and drug administration for the treatment of malignant tumors, but clinical results show that the objective effective rate of ICB single drug treatment is only 10% to 30% in most, non-selected solid tumors, and that most patients cannot benefit from it, namely primary drug resistance, even if treatment-effective patients develop disease progression, namely secondary drug resistance, after a period of treatment. With the advent of more ICB drugs, the medicine population is gradually increased, and it is important to find effective curative effect prediction markers and establish relevant prediction models, so that not only can the tumor response rate be improved, but also the treatment cost and time cost are saved for patients, a personalized diagnosis and treatment strategy is provided for the treatment of tumor patients, and the life time and life quality of the patients are improved.
It is known that early tumor cells express and produce certain abnormal proteins which can be recognized by the immune system of the organism to produce specific antibodies, the proteins are called tumor-related antigens, the antibodies are called autoantibodies, the antibodies are relatively more studied in autoimmune diseases, and in recent years, the early tumor cells have certain research in disease screening, early diagnosis, prognosis judgment and curative effect monitoring of tumors and show great potential. Compared with other markers, the serum autoantibody has a simple material obtaining way, and can be continuously sampled and monitored in the treatment process, so that the ICB curative effect prediction by utilizing the serum autoantibody has certain advantages. Early researches respectively adopt SEREX (recombinant cDNA expression library serological screening) method, phage peptide library panning method, SERPA (seroproteomics) method and the like to screen tumor autoantibodies, and a batch of disclosed tumor autoantibodies are used for diagnosing tumors at present. Wherein autoantibodies such as NY-SEO-1, p53, annexin I, 14-3-3 theta, LAMR1, PGP9.5, c-myc, HER2, CAGE, GBU-4-5, SOX2 and the like are used for lung cancer diagnosis; autoantibodies such as p53, HSP70, HCC-22-5, peroxiredoxin VI, KM-HN-1, and p90 are used for diagnosing gastric cancer; autoantibodies such as p62 and HCC1 are used for liver cancer diagnosis; autoantibodies such as Interleukin-29 (IL 29), survivin (SUR), growth horone (GRH), osteoprotegerin (OPG), and Resistin (RES) are used for diagnosis of breast cancer. Regarding the relationship between autoantibodies and ICB therapeutic effects, studies have been reported to report the relationship between the production of autoantibodies and ICB therapeutic toxic side effects, and the autoantibody levels have a certain relationship with ICB therapeutic effects.
Eukaryotic translation initiation factor 4E (eukaryotic translation initiation factor E, EIF 4E) is a cap binding protein which can specifically identify the cap structure of the 5' end of mRNA and plays an important role in the initiation process of eukaryotic translation. EIF4E is one of the factors closely related to malignancy, is highly expressed in a variety of human malignancies, and is closely related to tumor genesis, infiltration, and metastasis. For example: literature: the expression and meaning of EIF4E in liver cancer tissue are superior to those of other liver cancer tissue and normal liver tissue, and its expression is independent of patient's own condition, tumor size and coating completion, and is related to liver cancer differentiation, clinical stage and presence or absence of portal vein cancer embolism, because EIF4E protein expression is raised with the decrease of liver cancer differentiation, EIF4E can be used for diagnosis and treatment of liver cancer. Patent CN106460064a discloses a method for determining prognosis of patients suffering from high grade serous ovarian cancer (HG-SOC), said method comprising determining mutations of the ANKHD1-eIF4EBP3 isogene. Literature: research progress of EIF4E in cervical cancer, modern oncology, discloses that EIF4E expression in cervical tumors is increased and HPV E7 protein expression can be promoted, and the increase of cervical tissue malignancy is accompanied by the increase of EIF4E expression, so EIF4E is a potential marker for diagnosis and prognosis of cervical cancer. However, there are still many tumor diseases in which EIF4E is low expressed, and at the same time, no EIF4E or EIF4E autoantibodies have been disclosed as ICB treatment tumors or as therapeutic markers for autoimmune diseases.
Literature: the expression of the CCDC8 gene in breast cancer is Li Yunfen, tumor research and clinic, and the quantitative reverse transcription polymerase chain reaction is adopted to analyze the expression condition of the CCDC8 in 40 breast cancer combinations and 22 benign breast tumor tissues, and the result shows that the expression quantity of the CCDC8 gene in the benign breast tumor is obviously higher than that in the breast cancer tissues, and the expression has statistical significance. Because CCDC8 is expressed in breast tumor tissue and the expression level of malignant tissue is lower than that of benign tissue, the expression of CCDC8 has correlation with age, tumor size and nm23, so CCDC8 may be an oncogene of breast cancer to influence the occurrence and development of breast cancer. Literature: the functional research, yellow crystal and the like of the novel molecule CCDC134 prove that the CCDC134 is used as a potential cytokine, plays an important role in tumor immunity and autoimmune diseases and has potential application value. Literature: the expression and clinical significance of the CCDC67 gene in papillary thyroid carcinoma, lei Mengyuan, zhengzhou university's major institute paper, and the analysis of the expression of CCDC67mRNA and protein in differentiated thyroid carcinoma cell lines by real-time fluorescent quantitative PCR technology and cellular immunofluorescence technology, determine the effect of the CCDC67 gene in thyroid tumor. Literature: silencing the influence of DDX49 gene on osteosarcoma cell proliferation, the university of Lanzhou, research institute paper, discloses detecting the expression of DDX49 gene to determine its effect in osteosarcoma cell proliferation and apoptosis, and provides new molecular targets for diagnosis and treatment of osteosarcoma. However, the prior art is characterized in that the single autoantibody is used as a target to be used as a potential marker for diagnosis or prognosis, and the sensitivity and the specificity are limited; and the use of combinations of EIF4E2, CCDC130, UBALD1, LPCAT4 and/or VMAC autoantibodies, combinations of FATE1, EIF4E2, CCDC130, LPCAT4 and/or VMAC autoantibodies, and combinations of CPLX2, DDX49, phastr 1, EIF4E2 and VMAC autoantibodies in the preparation of a product for efficacy prediction or prognosis assessment of a tumor or autoimmune disease has not been disclosed.
Disclosure of Invention
The inventor successfully detects the levels of CPLX2, DDX49, PHACTR1, FATE1, UBILD 1, EIF4E2, CCDC130, LPCAT4 and VMAC autoantibodies in the blood of tumor or autoimmune disease patients through a rapid double-antibody sandwich enzyme-linked immunosorbent assay (rapid-ELISA), and the levels of the autoantibodies in the same serum sample are different, so that in high-autoantibody patients, more patients with good curative effects on immunotherapy are provided, and the autoantibodies can be used as markers for potential tumor diagnosis, curative effect prediction and prognosis evaluation of immunotherapy.
It is an object of the present invention to provide the use of an agent for detecting autoantibodies in the manufacture of a product for diagnosis, treatment and/or prognosis of a tumour, autoimmune disease, and the use of autoantibodies in the manufacture of a product for diagnosis, treatment and/or prognosis of a tumour, autoimmune disease.
It is another object of the present invention to provide a marker for diagnosis, treatment and/or prognostic evaluation of tumors, autoimmune diseases.
It is a further object of the present invention to provide a product for diagnosis, treatment and/or prognostic evaluation of tumors, autoimmune diseases.
It is still another object of the present invention to provide a method for detecting autoantibodies.
It is yet another object of the present invention to provide a method for diagnosis, treatment and/or prognostic evaluation of tumors, autoimmune diseases.
In a first aspect, the present invention provides the use of an agent for detecting an autoantibody selected from one of the following groups:
(1)EIF4E2；
(2)EIF4E2、CCDC130、UBALD1、LPCAT4、VMAC；
(3)EIF4E2、CCDC130、FATE1、LPCAT4、VMAC；
(4)CPLX2、DDX49、PHACTR1、EIF4E2、VMAC；
(5)EIF4E2、CCDC130、LPCAT4、VMAC；
(6)UBALD1；
(7)FATE1；
(8)EIF4E2、UBALD1；
(9)EIF4E2、FATE1；
(10)CPLX2、DDX49、PHACTR1；
(11)EIF4E2、VMAC。
preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the tumor is a lymphoma.
Preferably, the autoantibody comprises one or a combination of more than two of the autoantibody subtypes IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
Preferably, the autoantibody is an autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the autoantibodies are autoantibodies in serum and/or plasma.
Preferably, the detection of autoantibodies is the detection of the presence or absence of autoantibodies, or the level of expression.
Preferably, the method for detecting the autoantibody by using the reagent for detecting the autoantibody is selected from one or more than two of ELISA, rapid-ELISA, immunoblotting, indirect immunofluorescence, enzyme immunospot or immunoluminescence.
In one embodiment of the invention, the method for detecting autoantibodies by using the reagent for detecting autoantibodies is rapid-ELISA.
In a second aspect, the invention provides the use of an agent for detecting an autoantibody selected from one of the following groups:
(1)EIF4E2；
(2)EIF4E2、CCDC130、UBALD1、LPCAT4、VMAC；
(3)EIF4E2、CCDC130、FATE1、LPCAT4、VMAC；
(4)CPLX2、DDX49、PHACTR1、EIF4E2、VMAC；
(5)EIF4E2、CCDC130、LPCAT4、VMAC；
(6)UBALD1；
(7)FATE1；
(8)EIF4E2、UBALD1；
(9)EIF4E2、FATE1；
(10)CPLX2、DDX49、PHACTR1；
(11)EIF4E2、VMAC。
preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the tumor is a lymphoma.
Preferably, the autoantibody comprises one or a combination of more than two of the autoantibody subtypes IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
Preferably, the prognosis evaluation of tumor treatment is that of treatment with an immune checkpoint inhibitor or that of treatment with a combination of an immune checkpoint inhibitor and other drugs, radiotherapy, chemotherapy, etc.
Preferably, the autoantibody is an autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the autoantibodies are autoantibodies in serum and/or plasma.
Preferably, the detection of autoantibodies is the detection of the presence or absence of autoantibodies, or the level of expression.
Preferably, the method for detecting the autoantibody by using the reagent for detecting the autoantibody is selected from one or more than two of ELISA, rapid-ELISA, immunoblotting, indirect immunofluorescence, enzyme immunospot or immunoluminescence.
In one embodiment of the invention, the method for detecting autoantibodies by using the reagent for detecting autoantibodies is rapid-ELISA.
In a third aspect, the present invention provides the use of an autoantibody selected from one of the following groups in the manufacture of a product for the diagnosis and/or treatment of a tumour, autoimmune disease:
(1)EIF4E2；
(2)EIF4E2、CCDC130、UBALD1、LPCAT4、VMAC；
(3)EIF4E2、CCDC130、FATE1、LPCAT4、VMAC；
(4)CPLX2、DDX49、PHACTR1、EIF4E2、VMAC；
(5)EIF4E2、CCDC130、LPCAT4、VMAC；
(6)UBALD1；
(7)FATE1；
(8)EIF4E2、UBALD1；
(9)EIF4E2、FATE1；
(10)CPLX2、DDX49、PHACTR1；
(11)EIF4E2、VMAC。
preferably, the autoantibody comprises one or a combination of more than two of the autoantibody subtypes IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the tumor is a lymphoma.
Preferably, the autoantibody is an autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the autoantibodies are autoantibodies in serum and/or plasma.
In a fourth aspect, the invention provides the use of an autoantibody selected from one of the following groups in the manufacture of a product for prognosis evaluation of treatment of a tumour or autoimmune disease:
(1)EIF4E2；
(2)EIF4E2、CCDC130、UBALD1、LPCAT4、VMAC；
(3)EIF4E2、CCDC130、FATE1、LPCAT4、VMAC；
(4)CPLX2、DDX49、PHACTR1、EIF4E2、VMAC；
(5)EIF4E2、CCDC130、LPCAT4、VMAC；
(6)UBALD1；
(7)FATE1；
(8)EIF4E2、UBALD1；
(9)EIF4E2、FATE1；
(10)CPLX2、DDX49、PHACTR1；
(11)EIF4E2、VMAC。
preferably, the autoantibody comprises one or a combination of more than two of the autoantibody subtypes IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the tumor is a lymphoma.
Preferably, the prognosis of tumor treatment is that of treatment with an immune checkpoint inhibitor, or that of treatment with a combination of an immune checkpoint inhibitor and other drugs, radiation therapy, chemotherapy, etc.
Preferably, the autoantibody is an autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the autoantibodies are autoantibodies in serum and/or plasma.
In a fifth aspect of the present invention, there is provided a marker for diagnosis and/or treatment of a tumour, an autoimmune disease, said marker comprising an autoantibody selected from one of the group consisting of:
(1)EIF4E2；
(2)EIF4E2、CCDC130、UBALD1、LPCAT4、VMAC；
(3)EIF4E2、CCDC130、FATE1、LPCAT4、VMAC；
(4)CPLX2、DDX49、PHACTR1、EIF4E2、VMAC；
(5)EIF4E2、CCDC130、LPCAT4、VMAC；
(6)UBALD1；
(7)FATE1；
(8)EIF4E2、UBALD1；
(9)EIF4E2、FATE1；
(10)CPLX2、DDX49、PHACTR1；
(11)EIF4E2、VMAC。
preferably, the autoantibody comprises one or a combination of more than two of the autoantibody subtypes IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the tumor is a lymphoma.
Preferably, the autoantibody is an autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the autoantibodies are autoantibodies in serum and/or plasma.
In one embodiment of the present invention, the marker may further comprise other immune checkpoint proteins or autoantibodies other than CPLX2, DDX49, phastr 1, rate 1, UBALD1, EIF4E2, CCDC130, LPCAT4 and/or VMAC autoantibodies as accompanying markers for detection of the therapeutic effect of a tumor or autoimmune disease in combination with CPLX2, DDX49, phastr 1, rate 1, UBALD1, EIF4E2, CCDC130, LPCAT4 and/or VMAC autoantibodies. Wherein the accompanying marker is selected from one or more than two of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD 160.
In a sixth aspect of the invention, there is provided a marker for prognosis evaluation of treatment of a tumor or autoimmune disease, said marker comprising an autoantibody selected from one of the following groups:
(1)EIF4E2；
(2)EIF4E2、CCDC130、UBALD1、LPCAT4、VMAC；
(3)EIF4E2、CCDC130、FATE1、LPCAT4、VMAC；
(4)CPLX2、DDX49、PHACTR1、EIF4E2、VMAC；
(5)EIF4E2、CCDC130、LPCAT4、VMAC；
(6)UBALD1；
(7)FATE1；
(8)EIF4E2、UBALD1；
(9)EIF4E2、FATE1；
(10)CPLX2、DDX49、PHACTR1；
(11)EIF4E2、VMAC。
preferably, the autoantibody comprises one or a combination of more than two of the autoantibody subtypes IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the tumor is a lymphoma.
Preferably, the prognosis evaluation of the tumor treatment is performed by adopting immune checkpoint inhibitor treatment or by adopting a combination of immune checkpoint inhibitor and other medicaments, radiotherapy, chemotherapy and other treatment means.
Preferably, the autoantibody is an autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the autoantibodies are autoantibodies in serum and/or plasma.
In one embodiment of the present invention, the marker may further comprise other immune checkpoint proteins or autoantibodies other than CPLX2, DDX49, PHACTR1, FATE1, UBILD 1, EIF4E2, CCDC130, LPCAT4 and/or VMAC autoantibodies as accompanying markers for prognostic evaluation detection of tumors or autoimmune diseases in combination with CPLX2, DDX49, PHACTR1, FATE1, UBILD 1, EIF4E2, CCDC130, LPCAT4 and/or VMAC autoantibodies. Wherein the accompanying marker is selected from one or more than two of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD 160.
In a seventh aspect, the present invention provides a product for the diagnosis and/or treatment of a tumour, an autoimmune disease, said product comprising an agent for detecting an autoantibody selected from one of the group consisting of:
(1)EIF4E2；
(2)EIF4E2、CCDC130、UBALD1、LPCAT4、VMAC；
(3)EIF4E2、CCDC130、FATE1、LPCAT4、VMAC；
(4)CPLX2、DDX49、PHACTR1、EIF4E2、VMAC；
(5)EIF4E2、CCDC130、LPCAT4、VMAC；
(6)UBALD1；
(7)FATE1；
(8)EIF4E2、UBALD1；
(9)EIF4E2、FATE1；
(10)CPLX2、DDX49、PHACTR1；
(11)EIF4E2、VMAC。
preferably, the autoantibody comprises one or a combination of more than two of the autoantibody subtypes IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the tumor is a lymphoma.
Preferably, the autoantibody is an autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the autoantibodies are autoantibodies in serum and/or plasma.
Preferably, the detection of autoantibodies is the detection of the presence or absence of autoantibodies, or the level of expression.
Preferably, the method for detecting the autoantibody by using the reagent for detecting the autoantibody is selected from one or more than two of ELISA, rapid-ELISA, immunoblotting, indirect immunofluorescence, enzyme immunospot or immunoluminescence.
In one embodiment of the invention, the method for detecting autoantibodies by using the reagent for detecting autoantibodies is rapid-ELISA.
Preferably, the product for diagnosing and/or treating tumor and autoimmune diseases can further comprise other immune checkpoint proteins or autoantibodies except CPLX2, DDX49, PHACTR1, FATE1, UBILD 1, EIF4E2, CCDC130, LPCAT4 and/or VMAC autoantibodies as accompanying markers, and can be combined with CPLX2, DDX49, PHACTR1, FATE1, UBILD 1, EIF4E2, CCDC130, LPCAT4 and/or VMAC autoantibodies for detecting the therapeutic effects of tumor and autoimmune diseases. Wherein the accompanying marker is selected from one or more than two of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD 160.
In an eighth aspect of the invention, there is provided a product for prognosis evaluation of treatment of a tumour or autoimmune disease, said product comprising an agent for detecting an autoantibody selected from one of the following groups:
(1)EIF4E2；
(2)EIF4E2、CCDC130、UBALD1、LPCAT4、VMAC；
(3)EIF4E2、CCDC130、FATE1、LPCAT4、VMAC；
(4)CPLX2、DDX49、PHACTR1、EIF4E2、VMAC；
(5)EIF4E2、CCDC130、LPCAT4、VMAC；
(6)UBALD1；
(7)FATE1；
(8)EIF4E2、UBALD1；
(9)EIF4E2、FATE1；
(10)CPLX2、DDX49、PHACTR1；
(11)EIF4E2、VMAC。
preferably, the autoantibody comprises one or a combination of more than two of the autoantibody subtypes IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the tumor is a lymphoma.
Preferably, the autoantibody is an autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the autoantibodies are autoantibodies in serum and/or plasma.
Preferably, the detection of autoantibodies is the detection of the presence or absence of autoantibodies, or the level of expression.
Preferably, the method for detecting the autoantibody by using the reagent for detecting the autoantibody is selected from one or more than two of ELISA, rapid-ELISA, immunoblotting, indirect immunofluorescence, enzyme immunospot or immunoluminescence.
In one embodiment of the invention, the method for detecting autoantibodies by using the reagent for detecting autoantibodies is rapid-ELISA.
Preferably, the product of the prognosis evaluation of the treatment of the tumor or autoimmune disease may further comprise detection of the prognosis evaluation of the treatment of the tumor, autoimmune disease in combination with CPLX2, DDX49, PHACTR1, FATE1, UBILD 1, EIF4E2, CCDC130, LPCAT4 and/or VMAC autoantibodies other than CPLX2, DDX49, PHACTR1, FATE1, UBILD 1, EIF4E2, CCDC130, LPCAT4 and/or VMAC autoantibodies or other immune checkpoint proteins or autoantibodies as accompanying markers. Wherein the accompanying marker is selected from one or more than two of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD 160.
In a ninth aspect of the present invention, there is provided a method for diagnosing a tumour or an autoimmune disease, said method comprising detecting the presence or level of expression of an autoantibody in an organism, said autoantibody being selected from one of the group consisting of:
(1)EIF4E2；
(2)EIF4E2、CCDC130、UBALD1、LPCAT4、VMAC；
(3)EIF4E2、CCDC130、FATE1、LPCAT4、VMAC；
(4)CPLX2、DDX49、PHACTR1、EIF4E2、VMAC；
(5)EIF4E2、CCDC130、LPCAT4、VMAC；
(6)UBALD1；
(7)FATE1；
(8)EIF4E2、UBALD1；
(9)EIF4E2、FATE1；
(10)CPLX2、DDX49、PHACTR1；
(11)EIF4E2、VMAC。
preferably, the autoantibody comprises one or a combination of more than two of the autoantibody subtypes IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the tumor is a lymphoma.
Preferably, the autoantibody is an autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the autoantibodies are autoantibodies in serum and/or plasma.
In a tenth aspect, the present invention provides a method for prognosis evaluation of treatment of a tumor or autoimmune disease, said method comprising detecting the presence or expression level of an autoantibody in a living body, said autoantibody being selected from one of the group consisting of:
(1)EIF4E2；
(2)EIF4E2、CCDC130、UBALD1、LPCAT4、VMAC；
(3)EIF4E2、CCDC130、FATE1、LPCAT4、VMAC；
(4)CPLX2、DDX49、PHACTR1、EIF4E2、VMAC；
(5)EIF4E2、CCDC130、LPCAT4、VMAC；
(6)UBALD1；
(7)FATE1；
(8)EIF4E2、UBALD1；
(9)EIF4E2、FATE1；
(10)CPLX2、DDX49、PHACTR1；
(11)EIF4E2、VMAC。
preferably, the autoantibody comprises one or a combination of more than two of the autoantibody subtypes IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the tumor is a lymphoma.
Preferably, the autoantibody is an autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the autoantibodies are autoantibodies in serum and/or plasma.
In an eleventh aspect, the present invention provides a method of treating a tumor or autoimmune disease, said method comprising administering to a patient suffering from a tumor an effective dose of an immune checkpoint inhibitor, or a combination of an immune checkpoint inhibitor and other agents and treatments such as radiation therapy, chemotherapy, wherein the expression of an autoantibody is detected from within the patient, said autoantibody being selected from one of the group consisting of:
(1)EIF4E2；
(2)EIF4E2、CCDC130、UBALD1、LPCAT4、VMAC；
(3)EIF4E2、CCDC130、FATE1、LPCAT4、VMAC；
(4)CPLX2、DDX49、PHACTR1、EIF4E2、VMAC；
(5)EIF4E2、CCDC130、LPCAT4、VMAC；
(6)UBALD1；
(7)FATE1；
(8)EIF4E2、UBALD1；
(9)EIF4E2、FATE1；
(10)CPLX2、DDX49、PHACTR1；
(11)EIF4E2、VMAC。
preferably, the autoantibody comprises one or a combination of more than two of the autoantibody subtypes IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor.
In one embodiment of the invention, the tumor is a lymphoma.
Preferably, the immune checkpoint inhibitor is selected from PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD160 inhibitor.
Preferably, the detection of autoantibody expression from the patient is detection of autoantibody expression from the patient's serum, plasma, interstitial fluid, cerebrospinal fluid or urine. The higher the expression level of the autoantibody, the better the combined treatment effect of the immune checkpoint inhibitor or the immune checkpoint inhibitor and other medicines and treatment means such as chemotherapy, radiotherapy and the like is adopted.
In one embodiment of the invention, the detection of autoantibodies from within the patient is the detection of autoantibodies from the patient's serum and/or plasma.
In a twelfth aspect of the present invention, there is provided a method for detecting autoantibodies, comprising coating the surface of a carrier with the corresponding protein, adding a sample to be detected, adding an enzyme and a substrate, and measuring the concentration.
Preferably, the autoantibody is selected from CPLX2, DDX49, PHACTR1, FATE1, UBILD 1, EIF4E2, CCDC130, LPCAT4 and/or VMAC.
Preferably, the autoantibody comprises one or a combination of more than two of the autoantibody subtypes IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD.
Preferably, the sample to be tested is biological serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
In one embodiment of the invention, the sample to be tested is biological serum.
Preferably, the sample to be tested is diluted with a dilution buffer before addition, and the dilution concentration is 1:100-1000.
More preferably, the dilution concentration is 1:150-500.
Preferably, the dilution concentration is 1:200-400.
In one embodiment of the present invention, the dilution buffer is milk; the milk is PBST diluted milk.
Preferably, the enzyme is an enzyme-labeled antibody. More preferably, the enzyme-labeled antibody is IgG.
In one embodiment of the invention, the substrate is TMB.
Preferably, the concentration measuring method is to measure the absorbance value of 450 nm.
In one embodiment of the invention, the method comprises:
1) Coating the capture antibody in a 96-well plate, and washing at4 ℃ overnight; diluting with milk, and sealing for 1-3 hr; preferably, the mixture is diluted with milk and then is closed for 2 hours;
simultaneously adding the corresponding plasmid into an in-vitro expression system, carrying out light-proof reaction for 1-3 hours, preferably 2 hours, diluting with milk, adding into a 96-well plate, and washing at room temperature for 0.5-2 hours, preferably 1 hour, wherein the in-vitro expression system is IVTT; preferably, the serum sample is diluted to 1:200-400 with milk;
2) Adding the diluted serum sample into a 96-well plate, incubating and washing; preferably the incubation time is 0.5-2 hours;
3) Adding fresh diluted anti-human IgG HRP enzyme-labeled antibody, incubating and washing; preferably the incubation time is 0.5-2 hours; more preferably, the incubation time is from 0.5 to 1 hour;
4) Adding a temporarily prepared TMB substrate, and developing in a dark place; adding sulfuric acid to terminate the reaction; preferably, the light-shielding color development time is 10-30 minutes;
5) The absorbance at 450nm was measured to determine the level of autoantibody expression in the sample.
The reagent for detecting the expression level of the autoantibody is selected from test strips, protein chips, magnetic beads, fluorescent reagents and the like. The detection principle adopts antigen-antibody combination, wherein the detection antigen is protein, polypeptide or antibody.
The product of the invention comprises the reagent for detecting the level of the autoantibody. Preferably, the product is selected from the group consisting of kits, mass spectrometry.
A kit for detecting an autoantibody comprising a reagent for detecting the level of an autoantibody.
A chip for detecting autoantibodies comprising a reagent for detecting the level of autoantibodies.
A kit for diagnosing and/or treating a tumor comprising reagents for detecting the level of CPLX2, DDX49, PHACTR1, rate 1, UBALD1, EIF4E2, CCDC130, LPCAT4 and/or VMAC autoantibodies and reagents for detecting other immune checkpoints. The other immune checkpoints are selected from one or more than two of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD 160. Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor. In one embodiment of the invention, the tumor is a lymphoma.
A kit for prognosis evaluation of tumor treatment, comprising reagents for detecting the level of CPLX2, DDX49, PHACTR1, rate 1, UBALD1, EIF4E2, CCDC130, LPCAT4 and/or VMAC autoantibodies and reagents for detecting other immune checkpoints. The other immune checkpoints are selected from one or more than two of PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD 160. Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor. In one embodiment of the invention, the tumor is a lymphoma.
The invention relates to diagnosing tumor, which is to diagnose whether the tumor is suffered from, or prognosis evaluation of tumor patients, or evaluation of the benefit degree of treatment of tumor patients with immune checkpoint inhibitors.
The tumor treatment according to the present invention is to determine whether or not to treat by an immune checkpoint inhibitor by detecting the expression level of CPLX2, DDX49, PHACTR1, FATE1, UBILD 1, EIF4E2, CCDC130, LPCAT4 and/or VMAC autoantibodies.
The tumor of the present invention is selected from the group consisting of lymphoma, non-small cell lung cancer, leukemia, ovarian cancer, breast cancer, endometrial cancer, colon cancer, rectal cancer, gastric cancer, bladder cancer, lung cancer, bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, liver and bile duct cancer, esophageal cancer, renal cancer, thyroid cancer, head and neck cancer, testicular cancer, glioblastoma, astrocytoma, melanoma, myelodysplastic syndrome, and sarcoma. Wherein the leukemia is selected from acute lymphoblastic (lymphoblastic) leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, plasma cell leukemia, and chronic myelogenous leukemia; the lymphoma is selected from hodgkin's lymphoma and non-hodgkin's lymphoma, including B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, T-cell lymphoma, and waldenstrom's macroglobulinemia; the sarcoma is selected from osteosarcoma, ewing sarcoma, leiomyosarcoma, synovial sarcoma, soft tissue sarcoma, angiosarcoma, liposarcoma, fibrosarcoma, rhabdomyosarcoma, and chondrosarcoma. Preferably, the tumor is selected from lymphoma, non-small cell lung cancer or soft tissue sarcoma tumor. In one embodiment of the invention, the tumor is a lymphoma.
The autoimmune disease described in the present invention is selected from organ specific autoimmune diseases and systemic autoimmune diseases. Wherein the organ specific autoimmune disease is selected from chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia accompanied by chronic atrophic gastritis, lung hemorrhagic nephritis syndrome, pemphigus vulgaris, pemphigoid, primary biliary cirrhosis, multiple cerebral spinal sclerosis, acute idiopathic polyneuritis, etc. The systemic autoimmune disease is selected from systemic lupus erythematosus, rheumatoid arthritis, cutaneous rheumatoid nodules, arteritis, pericarditis, scleritis, lymphadenitis, hepatosplenomegaly, neuropathy, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease or ulcerative colitis.
Drawings
Embodiments of the present invention are described in detail below with reference to the attached drawing figures, wherein:
fig. 1: the rapid-ELISA sandwich method is used for detecting the distribution of serum EIF4E2 autoantibodies of 117 tumor patients, wherein the specific tumor patients are lymphoma, lung cancer and soft tissue sarcoma.
Fig. 2: the distribution of the EIF4E2 autoantibodies in an effective immune treatment group and an ineffective immune treatment group, wherein the effective immune treatment group is a tumor immune treatment effective group, namely a response group, and the ineffective immune treatment group is a tumor immune treatment ineffective group, namely a non-response group.
Fig. 3: ROC curve of effect of EIF4E2 autoantibodies on efficacy prediction of immunotherapy.
Fig. 4: ELISA Sandwich method for detecting comparison of relative levels of EIF4E2, CCDC130, UBILD 1, LPCAT4 and VMAC autoantibodies in serum of lymphoma patients.
Fig. 5: ROC curves predicted efficacy of five autoantibodies, EIF4E2, CCDC130, UBALD1, LPCAT4, VMAC in combination for immunotherapy in 57 lymphoma training set patients.
Fig. 6: prediction of long-term survival in patients who were immunotherapy with five autoantibodies, EIF4E2, CCDC130, UBALD1, LPCAT4, VMAC, in combination with 57 lymphoma training set patients.
Fig. 7: the ROC curves were validated for the prediction of efficacy of five autoantibodies, EIF4E2, CCDC130, UBALD1, LPCAT4, VMAC, in combination with immunotherapy in 32 patients from the lymphoma test set.
Fig. 8: ELISA Sandwich method for detecting comparison of relative levels of EIF4E2, CCDC130, FATE1, LPCAT4 and VMAC autoantibodies in serum of lymphoma patients.
Fig. 9: ROC curves for efficacy prediction of five autoantibodies, EIF4E2, CCDC130, rate 1, LPCAT4, VMAC, in combination for immunotherapy in 57 lymphoma training set patients.
Fig. 10: prediction of long-term survival in patients who were immunotherapy with five autoantibodies, EIF4E2, CCDC130, rate 1, LPCAT4, VMAC, in combination with 57 lymphoma training set patients.
Fig. 11: the efficacy prediction of five autoantibodies, namely EIF4E2, CCDC130, FATE1, LPCAT4 and VMAC, in combination with treatment efficacy prediction of 32 patients in the lymphoma test set was verified on ROC curve.
Fig. 12: ELISA sandwich method for detecting comparison of relative levels of CPLX2, EIF4E2, DDX49, PHACTR1 and VMAC autoantibodies in serum of lymphoma patients.
Fig. 13: ROC curve of the prediction of the efficacy of the combination of five autoantibodies, CPLX2, EIF4E2, DDX49, PHACTR1 and VMAC, on the immunotherapy of 57 lymphoma training set patients.
Fig. 14: the combination of five autoantibodies, CPLX2, EIF4E2, DDX49, PHACTR1 and VMAC, predicts long-term survival in patients who were immunotherapy in 57 cases of lymphoma training set patients.
Fig. 15: CPLX2, EIF4E2, DDX49, PHACTR1, VMAC in combination with the efficacy prediction of treatment for 32 patients in the lymphoma test set.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
1. Sample collection
Serum samples were collected in tumor hospitals of the national academy of medical science, the median age of tumor patients was 34 (18-74) years, the ratio of men and women was 71:46, 89 of lymphoma patients, 16 of non-small cell lung cancer patients, and 12 of soft tissue sarcoma patients, all of which obtained informed consent. And confirming a tumor diagnosis result through a pathological result, and obtaining curative effect evaluation information by receiving PD-1 antibody immunotherapy for all patients.
Of these, the median age of 34 (18-69) years in 89 lymphoma patients, the ratio of male and female was 52:37, and the grouping was as follows:
1) Lymphoma treatment efficacy was classified into four classes according to the solid tumor efficacy evaluation criteria (RECIST 1.1), CR (complete remission), PR (partial remission), SD (disease stabilization), PD (disease progression), and the treatment efficacy was sequentially reduced. To evaluate the correlation between the efficacy of autoantibodies and immunotherapy in lymphoma patients, patients with 3 (CPLX 2, EIF4E2, DDX49, PHACTR1, VMAC), 4.5 (EIF 4E2, CCDC130, FATE1, LPCAT4, VMAC), 6 (EIF 4E2, CCDC130, UBILD 1, LPCAT4, VMAC) continued CR, PR, SD for one month and patients with PD for 3 months were assigned to the active group in combination with the previous literature report and actual efficacy.
2) The sera of 89 patients were randomly divided into training (57) and test (32) sets.
2. Detection method
Detecting protein: CPLX2, DDX49, PHACTR1, FATE1, UBILD 1, EIF4E2, CCDC130, LPCAT4 and/or VMAC
The steps are as follows: a rapid enzyme-linked immunosorbent assay (rapid-ELISA) was performed to assess the concentration of serum autoantibodies. The capture antibody IgG, anti-GST anti-body (10 ng/μl) was coated in 96-well plates, washed overnight at4 ℃, blocked with 50 μl of PBST diluted milk buffer (5% milk, tween 0.2%) for 2 hours, while the corresponding plasmid (1 ng/μl 50 μl) was coated in 96-well plates, washed overnight at4 ℃, added to the in vitro expression system IVTT, protected from light at 37 ℃ for 1.5 hours, diluted with milk, added to 96-well plates, reacted at room temperature for 1 hour, and washed. Serum samples were diluted in dilution buffer (dilution concentration 1:300) and 50 μl of diluted sample/well was added to a 96-well microtiter plate, incubated at 37 ℃ for 1 hour, and then washed. To each well, 50. Mu.L of freshly diluted anti-human IgG HRP-enzyme-labeled antibody (1:8000 dilution) was added, incubated at 37℃for 1 hour, and washed. Subsequently, 0.1mL of a temporarily prepared TMB substrate solution was added to each reaction well, developed at 37℃in the absence of light for 25 minutes, and the reaction was stopped by adding 50. Mu.L of 0.05M sulfuric acid to each well, and the signal was determined by measuring the absorbance at 450 nm.
3. Statistical analysis
The inter-group variable differences were compared using the Mann-Whitney U Test, with P <0.05 considered statistically significant.
4. Experimental results
1) The method can successfully detect the level of autoantibodies in the serum of tumor patients
The conditions of the ELISA were used to detect the expression level of EIF4E2 autoantibodies in the serum samples of 89 cases of lymphomas, 16 cases of non-small cell lung cancer and 12 cases of soft tissue sarcoma tumor patients, and simultaneously detect the levels of EIF4E2, CCDC130, UBILD 1, LPCAT4 and VMAC, the levels of EIF4E2, CCDC130, FATE1, LPCAT4 and VMAC autoantibodies and the levels of CPLX2, EIF4E2, DDX49, PHACTR1 and VMAC autoantibodies in the serum of 89 cases of tumor patients. The results show that the enzyme-linked immunosorbent assay method can be used for successfully detecting the relative levels of autoantibodies in serum of a tumor patient, the levels of EIF4E2 autoantibodies in serum of patients among different tumors (see figure 1), the levels of EIF4E2, CCDC130, UBALD1, LPCAT4 and VMAC autoantibodies (see figure 4), EIF4E2, CCDC130, FATE1, LPCAT4, VMAC autoantibodies (see figure 8) and CPLX2, EIF4E2, DDX49, PHACTR1 and VMAC autoantibodies in serum of patients are different, and the levels of different autoantibodies in serum of patients are different.
2) Relation between serum autoantibody level of tumor patient and therapeutic effect of immunotherapy
How to more effectively distinguish between effective and ineffective patients in tumor immunotherapy is a major problem to be solved in clinical urgency, so that OD values are first standardized and the relationship between serum CPLX2, DDX49, PHACTR1, FATE1, UBALD1, EIF4E2, CCDC130, LPCAT4 and/or VMAC autoantibody levels of lymphoma patients and PD1 immunotherapy is examined.
Analysis of the individual index EIF4E 2: the results of analysis of 89 lymphoma patients are shown in FIG. 2, and show that the EIF4E2 autoantibody level is higher than that of the non-responsive group in patients with good treatment effect.
Analysis of five autoantibodies of EIF4E2, CCDC130, UBALD1, LPCAT4, VMAC: the training set of 57 patients was analyzed, and the results are shown in FIG. 5, in which the serum autoantibody levels in lymphoma patients combined with the ability to predict PD-1 immunotherapy, the area under the curve can reach 0.75. Further, as shown in fig. 6, the survival of the effective and ineffective patients predicted by the combination index in 57 patients was found to be longer in the effective patients, indicating that the combination of five autoantibodies had a certain long-term prognostic ability.
Analysis of five autoantibodies of EIF4E2, CCDC130, far 1, LPCAT4, VMAC: the training set of 57 patients was analyzed, and the results are shown in FIG. 9, in which the serum autoantibody levels in lymphoma patients combined with the ability to predict PD-1 immunotherapy, the area under the curve can reach 0.73. Further, as shown in fig. 10, the survival of the effective and ineffective patients predicted by the combination index in 57 patients was found to be longer in the effective patients, indicating that the combination of five autoantibodies had a certain long-term prognostic ability.
Analysis of five autoantibodies to CPLX2, EIF4E2, DDX49, PHACTR1, VMAC: the training set of 57 patients was analyzed, and the results are shown in FIG. 13, in which the serum autoantibody levels in lymphoma patients combined with the ability to predict PD-1 immunotherapy, the area under the curve can reach 0.77. Further, as shown in fig. 14, the survival of the effective and ineffective patients predicted by the combination index in 57 patients was found to be longer in the effective patients, indicating that the combination of five autoantibodies had a certain long-term prognostic ability.
3) ROC curve of the effect of autoantibodies on the efficacy prediction of immunotherapy.
Patients with different curative effects are distinguished by using EIF4E2 index alone, and the area under the curve can reach 0.73 (see figure 3). The results of the validation of 32 test set patients using five autoantibodies of EIF4E2, CCDC130, UBILD 1, LPCAT4 and VMAC in combination are shown in FIG. 7, which demonstrates that the area under the curve can reach 0.70 when the five autoantibodies in combination are tested for the effect prediction of lymphoma immunotherapy. The results of the combined detection of five autoantibodies of EIF4E2, CCDC130, FATE1, LPCAT4 and VMAC on 32 test set patients are shown in FIG. 11, and the effect of the combined detection of the five autoantibodies on the prediction of the curative effect of lymphoma immunotherapy is proved, and the area under the curve can reach 0.62. The results of the combined detection of five autoantibodies of CPLX2, EIF4E2, DDX49, PHACTR1 and VMAC on 32 test patients are shown in FIG. 15, and the effect of the combined detection of the five autoantibodies on the prediction of the curative effect of lymphoma immunotherapy is proved to be achieved, wherein the area under the curve can reach 0.69. It can be seen that serum CPLX2, DDX49, PHACTR1, FATE1, UBILD 1, EIF4E2, CCDC130, LPCAT4, and VMAC autoantibody levels are potential tumor immunotherapy markers.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Claims (8)
1. Use of an autoantibody for the preparation of a product for prognosis evaluation of a diagnostic tumor or tumor treatment, wherein said tumor is selected from the group consisting of lymphomas, said autoantibody being selected from one of the following groups:
（1）EIF4E2；
(2) EIF4E2, CCDC130, UBALD1, LPCAT4 and VMAC;
(3) EIF4E2, CCDC130, rate 1, LPCAT4, and VMAC;
(4) CPLX2, DDX49, PHACTR1, EIF4E2 and VMAC;
(5) EIF4E2, CCDC130, LPCAT4, and VMAC;
(6) EIF4E2 and UBALD1;
(7) EIF4E2 and rate 1;
(8) EIF4E2 and VMAC.
2. The use of claim 1, wherein the autoantibody comprises one or more of the autoantibody subclasses IgG1, igG2, igG3, igG4, igA1, igA2, igM, igE or IgD; the autoantibody is in serum, plasma, interstitial fluid, cerebrospinal fluid or urine.
3. The use according to claim 1, wherein the prognosis of the tumour treatment is that of a combination of an immune checkpoint inhibitor and other drugs and radiotherapy or chemotherapy treatments.
4. The use according to claim 3, wherein the immune checkpoint inhibitor is selected from PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 or CD160 inhibitor.
5. The use of claim 1, wherein the product comprises an agent for detecting autoantibodies.
6. The method according to claim 5, wherein the method for detecting autoantibodies by using the reagent for detecting autoantibodies is one or more selected from ELISA, immunoblotting, indirect immunofluorescence, enzyme immunospot method and immunoluminescence.
7. The use according to claim 6, wherein the ELISA is a rapid-ELISA.
8. The use according to any one of claims 5 to 7, wherein the detection of autoantibodies is the detection of the presence or absence of autoantibodies, or the expression level.
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