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摘要
Данный обзор посвящен механизмам работы противоопухолевого иммунитета и особенностям его формирования. Ингибиторы контрольных точек иммунного ответа изменили парадигму лечения больных со злокачественными новообразованиями (ЗНО). Иммунотерапия при многих ЗНО показала превосходящую стандартные химиотерапевтические опции эффективность. В данной работе представлен обзор литературных данных о механизмах формирования специфического противоопухолевого иммунитета и резистентности ЗНО к препаратам контроля иммунных точек. Для определения эффективности применения ингибиторов контрольных точек в клинической практике широко распространены маркеры: PD-L1 статус и микросателлитная нестабильность. Результаты исследований показывают, что уровень экспрессии PD-L1 определяет эффективность иммунотерапии. Наличие высокой микросателлитной нестабильности определяет чувствительность к терапии ИКТ независимо от гистологического подтипа. Наличие статусов PD-L1 и MSI является показанием для назначения блокаторов PD1 и PD-L1. Даже при наличии MSI и высокой экспрессии PD-L1 у определенной группы пациентов отсутствует эффект от проводимой терапии, что указывает о резистентности и отсутствии специфического противоопухолевого иммунитета. V(D)J-рекомбинации ДНК обеспечивают продукцию разнообразных антигенных рецепторов в развивающихся Т- и В-лимфоцитах, что представляется ключевым фактором развития специфического противоопухолевого иммунитета. Для определения эффективности иммунотерапии следует рассмотреть количественные показатели TREC и KREC.
参考
Amodio V., Mauri G., Reilly N.M., et al. Mechanisms of immune escape and resistance to checkpoint inhibitor therapies in mismatch repair deficient metastatic colorectal cancers. Сancers. 2021; 13(11): 2638.-DOI: https://doi.org/10.3390/cancers13112638.
Schmid P., Rugo H.S., Adams S., et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020; 21(1): 44-59.-DOI: https://doi.org/10.1016/S1470-2045(19)30689-8.
Michielin O., van Akkooi A., Ascierto P., et al. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2019; 30(12).-DOI: https://doi.org/10.1093/annonc/mdz411.
Planchard D., Popat S., Kerr K., et al. Correction to: «Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.». Ann Oncol. 2019; 30(5): 863-70.-DOI: https://doi.org/10.1093/annonc/mdy474.
Chung H.C., Ros W., Delord J.P., et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2019; 37(17): 1470-8.-DOI: https://doi.org/10.1200/JCO.18.01265.
Stratigos A.J., Sekulic A., Peris K., et al. Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial. Lancet Oncol. 2021; 22(6): 848-57.-DOI: https://doi.org/10.1016/S1470-2045(21)00126-1.
Saada-Bouzid E., Peyrade F., Guigay J. Immunotherapy in recurrent and or metastatic squamous cell carcinoma of the head and neck. Current Opinion in Oncology. 2019; 31(3): 146-51.-DOI: https://doi.org/10.1097/CCO.0000000000000522.
Herbst R.S., Arkenau H.T., Santana-Davila R., et al. Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial. Lancet Oncol. 2019; 20(8): 1109-23.-DOI: https://doi.org/10.1016/S1470-2045(19)30458-9.
Robert C., Long G.V., Brady B., et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015; 372(4): 320-30.-DOI: https://doi.org/10.1056/NEJMoa1412082.
Hodi F.S., O’Day S.J., McDermott D.F., et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363(8): 711-23.-DOI: https://doi.org/10.1056/NEJMoa1003466.
van Dijk N., Gil-Jimenez A., Silina K., et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nature Medicine. 2020; 26(12): 1839-44.-DOI: https://doi.org/10.1038/s41591-020-1085-z.
Robert C., Schachter J., Long G.V., et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015; 372(26): 2521-32.-DOI: https://doi.org/10.1056/NEJMoa1503093.
Wolchok J.D., Chiarion-Sileni V., Gonzalez R., et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017; 377(14): 1345-56.-DOI: https://doi.org/10.1056/NEJMoa1709684.
Weber J., Mandala M., Del Vecchio M., et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017; 377(19): 1824-35.-DOI: https://doi.org/10.1056/NEJMoa1709030.
Eggermont A.M.M., Blank C.U., Mandala M., et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018; 378(19): 1789-801.-DOI: https://doi.org/10.1056/NEJMoa1802357.
Tjulandin S., Demidov L., Moiseyenko V., et al. Novel PD-1 inhibitor prolgolimab: expanding non-resectable/metastatic melanoma therapy choice. European Journal of Cancer (Oxford, England: 1990). 2021; 149: 222-32.-DOI: https://doi.org/10.1016/j.ejca.2021.02.030.
Torre L.A., Siegel R.L., Jemal A. Lung cancer statistics. Adv Exp Med Biol. 2015; 1-19.-DOI: https://doi.org/10.1007/978-3-319-24223-1_1.
Lahiri A., Maji A., Potdar P.D., et al. Lung cancer immunotherapy: progress, pitfalls, and promises. Molecular Cancer. 2023; 22(1).-DOI: https://doi.org/10.1186/s12943-023-01740-y.
Taube J.M., Klein A., Brahmer J.R., et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014; 20(19): 5064-74.-DOI: https://doi.org/10.1158/1078-0432.CCR-13-3271.
Ott P.A., Bang Y.J., Piha-Paul S.A., et al. T-cell–inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol. 2019; 37(4): 318-27.- DOI: https://doi.org/10.1200/JCO.2018.78.2276
Gao C., Li X., Ji Y., et al. CTLA-4 regulates T follicular regulatory cell differentiation and participates in intestinal damage caused by spontaneous autoimmunity. Biochem Biophys Res Commun. 2018; 505(3): 865-71.-DOI: https://doi.org/10.1016/j.bbrc.2018.09.182.
Zhao P., Li L., Jiang X., Li Q. Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. Journal of Hematology & Oncology. 2019; 12(1).-DOI: https://doi.org/10.1186/s13045-019-0738-1.
Le D.T., Uram J.N., Wang H., et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015; 372(26): 2509-20.-DOI: https://doi.org/10.1056/NEJMoa1500596.
Marcus L., Lemery S.J., Keegan P., Pazdur R. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin Cancer Res. 2019; 25(13): 3753-8.-DOI: https://doi.org/10.1158/1078-0432.CCR-18-4070.
Taube J.M., Klein A., Brahmer J.R., et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to Anti-PD-1 therapy. Clin Cancer Res. 2014; 20(19): 5064-74.-DOI: https://doi.org/10.1158/1078-0432.CCR-13-3271.
Cristescu R., Mogg R., Ayers M., et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy. Science. 2018; 362(6411): eaar3593.-DOI: https://doi.org/10.1126/science.aax1384.
Bagchi S., Yuan R., Engleman E.G. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol. 2021; 16(1): 223-49.-DOI: https://doi.org/10.1146/annurev-pathol-042020-042741.
Morad G., Helmink B.A., Sharma P., Wargo J.A. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. 2021; 184(21): 5309-37.-DOI: https://doi.org/10.1016/j.cell.2021.09.020.
Seto T., Sam D., Pan M. Mechanisms of primary and secondary resistance to immune checkpoint inhibitors in cancer. Medical Sciences. 2019; 7(2): 14.-DOI: https://doi.org/10.3390/medsci7020014.
Султанбаев А.В., Мусин Ш.И., Меньшиков К.В., et al. Роль хромосомных V(D)J рекомбинаций лимфоцитов в формировании противоопухолевого иммунитета и эффективности применения иммунотерапии. Молекулярная медицина. 2023; 21(4): 11-19.-DOI: https://doi.org/10.29296/24999490-2023-04-02. [Sultanbaev A.V., Musin Sh.I., Menshikov K.V., et al. The role of chromosomal V(D)J recombinations of lymphocytes in the formation of antitumor immunity and the effectiveness of immunotherapy. Molecular Medicine. 2023; 21(4): 11-19.-DOI: https://doi.org/10.29296/24999490-2023-04-02. (In Rus)].
Serana F., Chiarini M., Zanotti C., et al. Use of V(D)J recombination excision circles to identify T- and B-cell defects and to monitor the treatment in primary and acquired immunodeficiencies. J Transl Med. 2013; 11(1): 119.-DOI: https://doi.org/10.1186/1479-5876-11-119.
Toubert A., Glauzy S., Douay C., Clave E. Thymus and immune reconstitution after allogeneic hematopoietic stem cell transplantation in humans: never say never again. Tissue Antigens. 2012; 79(2): 83-9.-DOI: https://doi.org/10.1111/j.1399-0039.2011.01820.x.
Velardi E., Clave E., Arruda L.C.M., et al. The role of the thymus in allogeneic bone marrow transplantation and the recovery of the peripheral T-cell compartment. Seminars in Immunopathology. 2021; 43(1): 101-17.-DOI: https://doi.org/10.1007/s00281-020-00828-7.
Mensen A., Ochs C., Stroux A., et al. Utilization of TREC and KREC quantification for the monitoring of early T- and B-cell neogenesis in adult patients after allogeneic hematopoietic stem cell transplantation. J Transl Med. 2013; 11(1).-DOI: https://doi.org/10.1186/1479-5876-11-188.
Negative selection of lymphocytes. Cell. 1994; 76(2): 229-39.-DOI: https://doi.org/10.1016/0092-8674(94)90331-x.
Fry A.M., Jones L.A., Kruisbeek A.M., Matis L.A. Thymic requirement for clonal deletion during T cell development. Science (New York, NY). 1989; 246(4933): 1044-6.-DOI: https://doi.org/10.1126/science.2511630.
Hodes R.J., Sharrow S.O., Solomon A. Failure of T cell receptor V beta negative selection in an athymic environment. Science (New York, NY). 1989; 246(4933): 1041-4.-DOI: https://doi.org/10.1126/science.2587987.
Ghia P., ten Boekel E., Rolink A.G., Melchers F. B-cell development: a comparison between mouse and man. Immunol Today. 1998; 19(10): 480-5.-DOI: https://doi.org/10.1016/s0167-5699(98)01330-9.
Dik W.A., Pike-Overzet K., Floor Weerkamp, et al. New insights on human T cell development by quantitative T cell receptor gene rearrangement studies and gene expression profiling. J Exp Med. 2005; 201(11): 1715-23.-DOI: https://doi.org/10.1084/jem.20042524.
Kwok J.S.Y., Cheung S.K.F., Ho J.C.Y., et al. Establishing Simultaneous T cell receptor excision circles (TREC) and K-deleting recombination excision circles (KREC) quantification assays and laboratory reference intervals in healthy individuals of different age groups in Hong Kong. Frontiers in Immunology. 2020; 11.-DOI: https://doi.org/10.3389/fimmu.2020.01411.
Образцов И.В., Гордукова М.А., Цветкова Е.В., et al. Эксцизионные кольца V(D)J рекомбинации B- и T-клеток как показатели иммунологической реконституции у детей с острым лимфобластным лейкозом. Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2016; 15(4): 42-50.-DOI: https://doi.org/10.24287/1726-1708-2016-15-4-42-50. [Obraztsov I.V., Gordukova M.A., Tsvetkova E.V., et al. V(D)J excision rings of B- and T-cell recombination as indicators of immunological reconstitution in children with acute lymphoblastic leukemia. Issues of Hematology/Oncology and Immunopathology in Pediatrics. 2016; 15(4): 42-50.-DOI: https://doi.org/10.24287/1726-1708-2016-15-4-42-50. (In Rus)].
Sultanbaev A.V., Musin S., Menshikov K., et al. 99P Quantitative indicators of TREC and KREC excision rings in malignant neoplasms. ESMO Open. 2023; 8(1): 100957.-DOI: https://doi.org/10.1016/j.esmoop.2023.100957.
Hoolehan W., Harris J.C., Byrum J.N., et al. An updated definition of V(D)J recombination signal sequences revealed by high-throughput recombination assays. Nucleic Acids Res. 2022.-DOI: https://doi.org/10.1093/nar/gkac1038.
Корсунский И.А., Кудлай Д.А., Продеус А.П., et al. Неонатальный скрининг на первичные иммунодефицитные состояния и Т-/В-клеточные лимфопении как основа формирования групп риска детей с врожденными патологиями. Педиатрия им. Г.Н. Сперанского. 2020; 99(2): 8-15.-DOI: https://doi.org/10.24110/0031-403X-2020-99-2-8-15I.A. [Korsunsky I.A., Kudlay D.A., Prodeus A.P., et al. Neonatal screening for primary immunodeficiency conditions and T-/B-cell lymphopenia as the basis for the formation of risk groups for children with congenital pathologies. Pediatrics Journal named after G.N. Speransky. 2020; 99(2): 8-15.-DOI: https://doi.org/10.24110/0031-403X-2020-99-2-8-15I.A. (In Rus)].
Козлов В.А., Тихонова Е.П., Савченко А.А., et al. Клиническая иммунология. Практическое пособие для инфекционистов. Красноярск: Поликор. 2021; 563.-DOI: https://doi.org/10.17513/np.518. [Kozlov V.A., Tikhonova E.P., Savchenko A.A., et al. Clinical immunology. A practical guide for infectious disease specialists. Krasnoyarsk: Polikor. 2021; 563.-DOI: https://doi.org/10.17513/np.518. (In Rus)].
Ru H., Zhang P., Wu H. Structural gymnastics of RAG-mediated DNA cleavage in V(D)J recombination. Curr Opin Struct Biol. 2018; 53: 178-86.-DOI: https://doi.org/10.1016/j.sbi.2018.11.001.
Wu G.S., Bassing C.H. Inefficient V(D)J recombination underlies monogenic T cell receptor β expression. Proceedings of the National Academy of Sciences. 2020; 117(31): 18172-4.-DOI: https://doi.org/10.1073/pnas.2010077117.
Garon E.B., Rizvi N.A., Hui R., et al. Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer. N Engl J Med. 2015; 372(21): 2018-28.-DOI: https://doi.org/10.1056/NEJMoa1501824.
Daud A.I., Wolchok J.D., Robert C., et al. Programmed death-ligand 1 expression and response to the anti–programmed death 1 antibody pembrolizumab in melanoma. J Clin Oncol. 2016; 34(34): 4102-9.-DOI: https://doi.org/10.1200/JCO.2016.67.2477.
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