2658-6533Research Results in Biomedicine2658-653310.18413/2658-6533-2022-8-2-0-32718Genetics<strong>Germline mutations as possible biomarkers of immune checkpoint inhibitor therapy efficacy in patients with renal cell carcinoma (mini review)</strong><strong>Germline mutations as possible biomarkers of immune checkpoint inhibitor therapy efficacy in patients with renal cell carcinoma (mini review)</strong>GilyazovaIrina R.GilyazovaIrina R.gilyasova_irina@mail.ruAsadullinaDilara D.AsadullinaDilara D.dilara.asadullina@yandex.ruIvanovaElizaveta A.IvanovaElizaveta A.lissa987@yandex.ruRakhimovRadmir R.RakhimovRadmir R.radmir-rr@mail.ruIzmailovAdel A.IzmailovAdel A.izmailov75@mail.ruBermishevaMarina A.BermishevaMarina A.marina_berm@mail.ruGilyazovaGulshat R.GilyazovaGulshat R.gulshatik2001@mail.ruSharifgaleevIldar A.SharifgaleevIldar A.ildarado@bk.ruUrmantsevMarat F.UrmantsevMarat F.urmantsev85@mail.ruPopovaEkaterina V.PopovaEkaterina V.katusha-pv@mail.ruSafikhanovRishat Ya.SafikhanovRishat Ya.safikhanov_rishat@rambler.ruPavlovValentin N.PavlovValentin N.vpavlov3@yandex.ruKhusnutdinovaElza K.KhusnutdinovaElza K.elzakh@mail.ru20228200

Background:&nbsp;The use of immune checkpoint inhibitors (ICIs) is a promising therapy in cancer treatment, in particular renal cell carcinoma (RCC). Despite the revolutionary breakthrough in cancer treatment, a significant part of patients is resistant to ICIs. To date, the assessment of the PD-L1 protein expression level (programmed cell death receptor 1 ligand) on tumor cells is the only approved method for prescribing ICI therapy, however, this marker does not accurately predict the response to therapy. In this regard, the search for additional prognostic factors to control the treatment success of patients with ICI drugs based on complex genetic and epigenetic analysis is relevant. The aim of the study:&nbsp;To analyze and summarize the results of molecular genetic studies for the purpose of possible use as efficacy prognostic biomarkers when prescribing ICT drugs. Materials and methods:&nbsp;The review and analysis of Russian and foreign literature in the Pubmed, Scopus, Google Academy, Elibrary databases over the past 5 years was performed based on existing studies that allow to evaluate the possible effects of genetic polymorphisms on the ICI therapy efficacy and the resistance development. Results:&nbsp;Germline mutations in genes associated with the tumor microenvironment and PD-1, CTLA-4 genes, as well as heterozygous carriage of the human leukocyte antigen class I (HLA-I) gene were associated with improved efficacy and survival rates in patients receiving ICI therapy. Despite the relevant problem of the existing biomarkers failure in the immunotherapy administration, the role of molecular genetic features of cancer patients has been underexplored and requires further research in this area. Conclusion:&nbsp;Molecular genetic characteristics of patients play an important role in the therapy response, including antitumor therapy. The use of additional prognostic markers for ICIs therapy efficacy in patients with different tumor types will make it possible to personalize the approach in cancer treatment, increase the accuracy of candidate selection and reduce the risk of immune-mediated adverse events

Background:&nbsp;The use of immune checkpoint inhibitors (ICIs) is a promising therapy in cancer treatment, in particular renal cell carcinoma (RCC). Despite the revolutionary breakthrough in cancer treatment, a significant part of patients is resistant to ICIs. To date, the assessment of the PD-L1 protein expression level (programmed cell death receptor 1 ligand) on tumor cells is the only approved method for prescribing ICI therapy, however, this marker does not accurately predict the response to therapy. In this regard, the search for additional prognostic factors to control the treatment success of patients with ICI drugs based on complex genetic and epigenetic analysis is relevant. The aim of the study:&nbsp;To analyze and summarize the results of molecular genetic studies for the purpose of possible use as efficacy prognostic biomarkers when prescribing ICT drugs. Materials and methods:&nbsp;The review and analysis of Russian and foreign literature in the Pubmed, Scopus, Google Academy, Elibrary databases over the past 5 years was performed based on existing studies that allow to evaluate the possible effects of genetic polymorphisms on the ICI therapy efficacy and the resistance development. Results:&nbsp;Germline mutations in genes associated with the tumor microenvironment and PD-1, CTLA-4 genes, as well as heterozygous carriage of the human leukocyte antigen class I (HLA-I) gene were associated with improved efficacy and survival rates in patients receiving ICI therapy. Despite the relevant problem of the existing biomarkers failure in the immunotherapy administration, the role of molecular genetic features of cancer patients has been underexplored and requires further research in this area. Conclusion:&nbsp;Molecular genetic characteristics of patients play an important role in the therapy response, including antitumor therapy. The use of additional prognostic markers for ICIs therapy efficacy in patients with different tumor types will make it possible to personalize the approach in cancer treatment, increase the accuracy of candidate selection and reduce the risk of immune-mediated adverse events

immune checkpoint inhibitorsPD-1drug resistancerenal cell carcinomageneticsgermline mutationsimmune checkpoint inhibitorsPD-1drug resistancerenal cell carcinomageneticsgermline mutationsСписок литературыTung I, Sahu A. Immune Checkpoint Inhibitor in First-Line Treatment of Metastatic Renal Cell Carcinoma: A Review of Current Evidence and Future Directions. Frontiers in Oncology. 2021;11:707214. DOI: https://doi.org/10.3389/fonc.2021.707214Ross K, Jones RJ. Immune checkpoint inhibitors in renal cell carcinoma. Clinical Science. 2017;131(21):2627-2642. DOI: https://doi.org/10.1042/CS20160894Global Cancer Observatory [Internet] [cited 2022 Mar 15]. Available from: https://gco.iarc.fr/today/data/factsheets/cancers/29-Kidney-fact-sheet.pdfKaprin АD, Starinskogo VV, Shahzadov АО. The state of cancer care for the population of Russia in 2019. М.: МNIOI P.А. Gerzena; 2020.Chat V, Ferguson R, Kirchhoff T. Germline genetic host factors as predictive biomarkers in immuno-oncology. Immuno-Oncology and Technology. 2019;2:14-21. DOI: https://doi.org/10.1016/j.iotech.2019.08.001Sul J, Blumenthal GM, Jiang X, et al. FDA Approval Summary: pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1. Oncologist. 2016;21(5):643-650. DOI: https://doi.org/10.1634/theoncologist.2015-0498Pai-Scherf L, Blumenthal GM, Li H, et al. FDA Approval Summary: pembrolizumab for treatment of metastatic non-small cell lung cancer: first-line therapy and beyond. Oncologist. 2017;22(11):1392-1399. DOI: https://doi.org/10.1634/theoncologist.2017-0078Li H, Yu J, Liu C, et al. Time dependent pharmacokinetics of pembrolizumab in patients with solid tumor and its correlation with best overall response. Journal of Pharmacokinetics and Pharmacodynamics. 2017;44(5):403-414. DOI: https://doi.org/10.1007/s10928-017-9528-yLarkins E, Blumenthal GM, Yuan W, et al. FDA Approval Summary: pembrolizumab for the treatment of recurrent or metastatic head and neck squamous cell carcinoma with disease progression on or after platinum-containing chemotherapy. Oncologist. 2017;22(7):873-878. DOI: https://doi.org/10.1634/theoncologist.2016-0496Three drugs approved for urothelial carcinoma by FDA. Cancer Discovery. 2017;7(7):659-660. DOI: https://doi.org/10.1158/2159-8290.CD-NB2017-071Sheng J, Srivastava S, Sanghavi K, et al. Clinical pharmacology considerations for the development of immune checkpoint inhibitors. Journal of Clinical Pharmacology. 2017;57(s10):S26-S42. DOI: https://doi.org/10.1002/jcph.990Kazandjian D, Suzman DL, Blumenthal G, et al. FDA Approval Summary: nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy. Oncologist. 2016;21(5):634-642. DOI: https://doi.org/10.1634/theoncologist.2015-0507Weinstock C, Khozin S, Suzman D, et al. U.S. Food and Drug Administration Approval Summary: atezolizumab for metastatic non-small cell lung cancer. Clinical Cancer Research. 2017;23(16):4534-4539. DOI: https://doi.org/10.1158/1078-0432.CCR-17-0540Ning YM, Suzman D, Maher VE, et al. FDA Approval Summary: atezolizumab for the treatment of patients with progressive advanced urothelial carcinoma after platinum-containing chemotherapy. Oncologist. 2017;22(6):743-749. DOI: https://doi.org/10.1634/theoncologist.2017-0087Nod for atezolizumab in advanced bladder cancer. Cancer Discovery. 2017;7(6):OF4. DOI: https://doi.org/10.1158/2159-8290.CD-NB2017-064Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, singlegroup, open-label, phase 2 trial. The Lancet Oncology. 2016;17(10):1374-1385. DOI: https://doi.org/10.1016/S1470-2045(16)30364-3Syed YY. Durvalumab: first global approval. Drugs. 2017;77(12):1369-1376. DOI: https://doi.org/10.1007/s40265-017-0782-5Guo L, Wei R, Lin Y, et al. Clinical and Recent Patents Applications of PD-1/PD-L1 Targeting Immunotherapy in Cancer Treatment&mdash;Current Progress, Strategy, and Future Perspective. Frontiers in Immunology. 2020;11:1508. DOI: https://doi.org/ 10.3389/fimmu.2020.01508Chen Q, Li T, Yue W. Drug response to PD-1/PD-L1 blockade: based on biomarkers. OncoTargets and Therapy. 2018;11:4673-4683. DOI: https://doi.org/10.2147/OTT.S168313Gong J, Chehrazi-Raffle A, Reddi S, et al. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. Journal for ImmunoTherapy of Cancer. 2018;6(1):8. DOI: https://doi.org/10.1186/s40425-018-0316-zHavel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nature Reviews Cancer. 2019;19(3):133-150. DOI: https://doi.org/10.1038/s41568-019-0116-xWeiss SA, Wolchok JD, Sznol M. Immunotherapy of Melanoma: Facts and Hopes. Clinical Cancer Research. 2019;25(17):5191-5201. DOI: https://doi.org/10.1158/1078-0432.CCR-18-1550Dempke WCM, Fenchel K, Uciechowski P, Dale SP. Second- and third-generation drugs for immuno-oncology treatment-The more the better? European Journal of Cancer. 2017;74:55-72. DOI: https://doi.org/10.1016/j.ejca.2017.01.001Refae S, Gal J, Ebran N, et al. Germinal Immunogenetics predict treatment outcome for PD1/PD-L1 checkpoint inhibitors. Investigational New Drugs. 2020;38(1):160-171. DOI: https://doi.org/10.1007/s10637-019-00845-wMcGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463-1469. DOI: https://doi.org/10.1126/science.aaf1490Chen P, Roh W, Reuben A, et al. Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade. Cancer Discovery. 2016;6(8):827-837. DOI: https://doi.org/10.1158/2159-8290.CD-15-1545Topalian SL, Taube JM, Anders RA, et al. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nature Reviews Cancer. 2016;16(5):275-287. DOI: https://doi.org/10.1038/nrc.2016.36Tian С, Hromatka BS, Kiefer AK, et al. Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections. Nature. Communications. 2017;8:599. DOI: https://doi.org/10.1038/s41467-017-00257-5Gordiev MG, Brovkina OI, Enikeev RF, et al. Guidelines for the interpretation of clinically significant somatic mutations in solid tumors identified by next generation sequencing (NGS) for their clinical use. М.: Obshcherossiyskaya obshchestvennaya organizatsiya &laquo;Rossiyskoye obshchestvo klinicheskoy onkologii; 2020. Russian.Baranova EE, Bodunova NA, Vorontsova МV, et al. Hereditary cancer syndromes: a modern paradigm. Problems of Endocrinology. 2020;66(4):24-34. Russian. DOI: https://doi.org/10.14341/probl12366Carter H, Marty R, Hofree M, et al. Interaction Landscape of Inherited Polymorphisms with Somatic Events in Cancer. Cancer Discovery. 2017;7(4):410-423. DOI: https://doi.org/10.1158/2159-8290.CD-16-1045Yurgelun MB, Chenevix-Trench G, Lippman SM. Translating Germline Cancer Risk into Precision Prevention. Cell. 2017;168(4):566-570. DOI: https://doi.org/10.1016/j.cell.2017.01.031Tait Wojno ED, Hunter CA, Stumhofer JS. The Immunobiology of the Interleukin-12 Family: Room for Discovery. Immunity. 2019;50(4):851-870. DOI: https://doi.org/10.1016/j.immuni.2019.03.011Johdi NA, Mazlan L, Sagap I, et al. Profiling of cytokines, chemokines and other soluble proteins as a potential biomarker in colorectal cancer and polyps. Cytokine. 2017;99:35-42. DOI: https://doi.org/10.1016/j.cyto.2017.06.015Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nature Reviews Immunology. 2017;17:559-572. DOI: https://doi.org/10.1038/nri.2017.49Korbecki J, Kojder K, Simińska D, et al. CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of the Ligands of Receptors CCR1, CCR2, CCR3, and CCR4. International Journal of Molecular Sciences. 2020;21(21):8412. DOI: https://doi.org/10.3390/ijms21218412Svitich OA, Filina AB, Davydova NV, et al. The role of innate immunity factors in tumorigenesis process. Medical Immunology (Russia). 2018;20(2):151-162. Russian. DOI: https://doi.org/10.15789/1563-0625-2018-2-151-162Patin E, Hasan M, Bergstedt J, et al. Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors. Nature Immunology. 2018;19(3):302-314. DOI: https://doi.org/10.1038/s41590-018-0049-739.Urrutia A, Duffy D, Rouilly V, et al. Standardized Whole-Blood Transcriptional Profiling Enables the Deconvolution of Complex Induced Immune Responses. Cell Reports. 2016;16(10):2777-2791. DOI: https://doi.org/10.1016/j.celrep.2016.08.011Nomizo T, Ozasa H, Tsuji T, et al. Clinical impact of single nucleotide polymorphism in PD-L1 on response to nivolumab for advanced nonsmall-cell lung cancer patients. Scientific Reports. 2017;7:45124. DOI: https://doi.org/10.1038/srep45124Refae S, Gal J, Brest P, et al. Germinal immunogenetics as a predictive factor for immunotherapy. Critical Reviews in Oncology/Hematology. 2019;141:146-152. DOI: https://doi.org/10.1016/j.critrevonc.2019.06.013Yeo MK, Choi SY, Seong IO, et al. Association of PD-L1 expression and PD-L1 gene polymorphism with poor prognosis in lung adenocarcinoma and squamous cell carcinoma. Human Pathology. 2017;68:103-111. DOI: https://doi.org/10.1016/j.humpath.2017.08.016Lee SY, Jung DK, Choi JE, et al. Functional polymorphisms in PD-L1 gene are associated with the prognosis of patients with early stage non-small cell lung cancer. Gene. 2017;599:28-35. DOI: https://doi.org/10.1016/j.gene.2016.11.007Minari R, Bonatti F, Mazzaschi G, et al. PD-L1 SNPs as biomarkers to define benefit in patients with advanced NSCLC treated with immune checkpoint inhibitors. Tumori Journal. 2022;108(1):47-55. DOI: https://doi.org/10.1177/03008916211014954Chat V, Ferguson R, Simpson D, et al. Autoimmune genetic risk variants as germline biomarkers of response to melanoma immune-checkpoint inhibition. Cancer Immunology, Immunotherapy. 2019;68(6):897-905. DOI: https://doi.org/10.1007/s00262-019-02318-8Parakh S, Musafer A, Paessler S, et al. PDCD1 Polymorphisms May Predict Response to Anti-PD-1 Blockade in Patients With Metastatic Melanoma. Frontiers in Immunology. 2021;2:672521. DOI: https://doi.org/10.3389/fimmu.2021.672521With MD, Hurkmans DP, Oomen-de Hoop E, et al. Germline Variation in PDCD1 Is Associated with Overall Survival in Patients with Metastatic Melanoma Treated with аnti-PD-1 Monotherapy Germline genetic host factors as predictive biomarkers in immuno-oncology. Cancers. 2021;13(6):1370. DOI: https://doi.org/10.3390/cancers13061370Queirolo P, Dozin B, Morabito A, et al. Association of CTLA-4 Gene Variants with Response to Therapy and Long-term Survival in Metastatic Melanoma Patients Treated with Ipilimumab: An Italian Melanoma Intergroup Study. Frontiers in Immunology. 2017;8:386. DOI: https://doi.org/10.3389/fimmu.2017.00386Chowell D, Morris LGT, Grigg CM, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science. 2018;359(6375):582-587. DOI: https://doi.org/10.1126/science.aao4572Kvistborg P, Yewdell JW. Enhancing responses to cancer immunotherapy. Science. 2018;359(6375):516-517. DOI: https://doi.org/10.1126/science.aar6574Chowell D, Krishna C, Pierini F, et al. Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy. Nature Medicine. 2019;25(11):1715-1720. DOI: https://doi.org/10.1038/s41591-019-0639-4Ali OH, Berner F, Bomze D, et al. Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors. European Journal of Cancer. 2019;107:8-14. DOI: https://doi.org/10.1016/j.ejca.2018.11.009