О.В. Ковалёва1, В.В. Масленников2, Н.Ю. Соколов3, М.М. Конторщиков4, 

А.С. Мочалова5, Н.Е Кушлинский6

1,3,5,6 ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» 

Минздрава России (Москва, Россия)

2 МГМСУ им. А.И. Евдокимова Минздрава России (Москва, Россия)

4 Приволжский исследовательский медицинский университет (г. Нижний Новгород, Россия)

Постановка проблемы. Колоректальный рак (КРР) – одна из широко распространенных опухолей желудочно-кишечного тракта, занимающая четвертое место по заболеваемости среди всех злокачественных новообразований в мире. В настоящее время предпринимаются попытки иммунотерапии КРР препаратами, блокирующими одну из ключевых контрольных точек иммунитета – PD1/PD-L1, с учетом экспрессии рецептора программируемой гибели клетки PD-1 и его лиганда PD-L1 в опухоли. Однако, несмотря на успехи иммунотерапии, достигнутые в лечении многих других злокачественных новообразований, КРР крайне тяжело поддается данному типу терапии.

Цель работы – анализ современных исследований, посвященных клинической значимости экспрессии PD-1 и PD-L1 в опухолях толстой кишки и особенностей механизмов их взаимодействия, препятствующих успешной терапии данной патологии иммунопрепаратами.

Результаты. Механизм действия иммунологических препаратов направлен на разрушение системы PD-1/PD-L1. Наиболее важным условием их применения прежде всего является определение у больных соответствующих мишеней: рецептора PD-1 или его лигандов PD-L1, PD-L2. В данном обзоре описано строение функции системы PD-1/PD-L1 в норме и при патологии. Отдельное внимание уделено изучению экспрессии PD-1, PD-L1 в опухоли (как непосредственно опухолевыми, так и иммунокомпетентными клетками, инфильтрирующими первичную опухоль) и их растворимых форм (sPD-1, sPD-L1) в сыворотке крови онкологических пациентов. Описано, что как предиктор выживаемости уровень экспрессии PD-L1 в самой опухоли неустойчив и не очень информативен. В то же время высокий уровень экспрессии PD-L1 в ее окружении достоверно коррелирует с лучшим прогнозом. Представлены первые результаты по изучению sPD-1 и sPD-L1 у больных КРР. Представлены данные о результатах проводимой анти-PD-1/PD-L терапии при разных типах опухолей толстой кишки. Описаны современные препараты, действие которых направлено на PD-1/PD-L1 и успехи их применения, как в режиме монотерапии, так и в комбинации с другими лекарственными агентами.

Практическая значимость. Уровень экспрессии PD-1, PD-L1 в опухоли и растворимых форм данных белков sPD-1 и sPD-L1 в сыворотке крови больных КРР коррелирует с некоторыми клиническими и морфологическими характеристиками опухоли и может рассматриваться в качестве потенциального маркера для мониторинга эффективности анти-PD-1/PD-L1 терапии и оценки прогноза выживаемости пациентов.

Ковалёва О.В., Масленников В.В., Соколов Н.Ю., Конторщиков М.М., Мочалов А.С., Кушлинский Н.Е. Клиническая значимость ключевой точки иммунитета PD-1/PD-L1 при колоректальном раке // Технологии живых систем. 2021. T. 18. № 3. С. 5−26. DOI: https://doi.org/10.18127/j20700997-202103-01

1. Torre L.A., Bray F., Siegel R.L., Ferlay J., Lortet‐Tieulent J., Jemal A. Global cancer statistics, 2012 // CA Cancer J. Clin. 2015.  V. 65. № 2. P. 87-108.
2. Haggar F.A., Boushey R.P. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors // Clin. Colon Rectal Surg. 2009. V. 22. № 4. P. 191–197.
3. Brenner H., Kloor M., Pox C.P. Colorectal cancer // Lancet. 2014. V. 383. № 9927. P. 1490–1502.
4. Elez E., Argiles G., Tabernero J. First-line treatment of metastatic colorectal cancer: interpreting FIRE-3, PEAK, and CALGB/SWOG 80405 // Curr. Treat. Options Oncol. 2015. V. 16. № 11. P. 52.
5. Wei F., Zhang T., Deng S.C., Wei J.C., Yang P., Wang Q., Chen Z.P., Li W.L., Chen H.C., Hu H., Cao J. PD-L1 promotes colorectal cancer stem cell expansion by activating HMGA1-dependent signaling pathways // Cancer Lett. 2019. V. 450. P. 1-13.
6. Cui C., Yu B., Jiang Q., Li X., Shi K., Yang Z. The roles of PD-1/PD-L1 and its signaling pathway in gastrointestinal tract cancers // Clin. Exp. Pharmacol. Physiol. 2019. V. 46. № 1. P. 3-10.
7. Huang K.C., Chiang S.F., Chen W.T., Chen T.W., Hu C.H., Yang P.C., Ke T.W., Chao K.S.C. Decitabine Augments ChemotherapyInduced PD-L1 Upregulation for PD-L1 Blockade in Colorectal Cancer // Cancers (Basel). 2020. V. 12. № 2. P. 462.
8. Payandeh Z., Khalili S., Somi M.H., Mard-Soltani M., Baghbanzadeh A., Hajiasgharzadeh K., Samadi N., Baradaran B. PD-1/PDL1-dependent immune response in colorectal cancer // J. Cell Physiol. 2020. V. 235. № 7-8. P. 5461-5475.
9. Noh B.J., Kwak J.Y., Eom D.W. Immune Classification for the PD-L1 Expression and Tumour-Infiltrating Lymphocytes in Colorectal Adenocarcinoma // BMC Cancer. 2020. V. 20. № 1. P. 58.
10. Quigley D.A., Kristensen V. Predicting prognosis and thera-peutic response from interactions between lymphocytes and tumor cells. Mol. Oncol. 2015. V. 9. № 10. P. 2054-2062.
11. Senovilla L., Galluzzi L., Zitvogel L., Kroemer G. Immunosurveillance as a regulator of tissue homeostasis // Trends Immunol. 2013. V. 34. № 10. P. 471-481.
12. Gubin M.M., Artyomov M.N., Mardis E.R., Schreiber R.D. Tu-mor neoantigens: building a framework for personalized cancer immunotherapy // J. Clin. Invest. 2015. V. 125. № 9. P. 3413-3421.
13. Olivera J. Finn Human Tumor Antigens Yesterday, Today, and Tomorrow Cancer Immunol Res. Author manuscript; available in PMC 2018 // Cancer Immunol. Res. 2017. V. 5. № 5. P. 347-354.
14. Кадагидзе З.Г., Черткова А.И. Иммунная система и рак // Практическая онкология. 2016. Т. 17. № 2. C. 62-73.
15. Finn O.J. Human Tumor Antigens Yesterday, Today, and Tomorrow // Cancer Immunol. Res. 2017. V. 5. № 5. P. 347-354.
16. Grünwald V. Checkpoint Blockade - a New Treatment Paradigm in Renal Cell Carcinoma // Oncol. Res. Treat. 2016. V. 39. № 6.  P. 353-358.
17. Lee J.Y., Lee H.T., Shin W., Chae J., Choi J., Kim S.H., Lim H., Won Heo T., Park K.Y., Lee Y.J., Ryu S.E., Son J.Y., Lee J.U., Heo Y.S. Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy // Nat. Commun. 2016. V. 7. P. 13354.
18. Schmidinger M. Clinical decision-making for immunotherapy in metastatic renal cell carcinoma // Curr. Opin. Urol. 2018. V. 28.  № 1. P. 29-34.
19. Mataraza J.M., Gotwals P. Recent advances in immunooncology and its application to urological cancers // BJU Int. 2016. V. 118.  № 4. P. 506-514.
20. Chen J., Jiang C.C., Jin L., Zhang X.D. Regulation of PD-L1: a novel role of pro-survival signalling in cancer // Ann. Oncol. 2016. V. 27. № 3. P. 409-416.
21. Sakamuri D., Glitza I.C., Betancourt Cuellar S.L., Subbiah V., Fu S., Tsimberidou A.M., Wheler J.J., Hong D.S., Naing A., Falchook G.S., Fanale M.A., Cabanillas M.E., Janku F. Phase 1 dose-escalation study of anti CTLA-4 antibody ipilimumab and lenalidomide in patients with advanced cancers // Mol. Cancer Ther. 2017. V. 17. № 3. P. 671-676.
22. Simmons D., Lang E. The Most Recent Oncologic Emergency: What Emergency Physicians Need to Know About the Potential Complications of Immune Checkpoint Inhibitors // Cureus. 2017. V. 9. № 10. e1774.
23. Румянцев А.Г., Тюляндин С.А. Эффективность ингибиторов контрольных точек иммунного ответа в лечении солидных опухолей // Практическая онкология. 2016. Т. 17. № 2. С. 74-89.
24. Ross K., Jones R.J. Immune checkpoint inhibitors in renal cell carcinoma // Clin. Sci. (Lond). 2017. V. 131. № 21. P. 2627-2642.
25. Ishida Y., Agata Y., Shibahara K., Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death // EMBO J. 1992. V. 11. № 11. P. 3887-3895.
26. Keir M.E., Butte M.J., Freeman G.J., Sharpe A.H. PD-1 and its ligands in tolerance and immunity // Annu. Rev. Immunol. 2008. V. 26. P. 677-704.
27. Shinohara T., Taniwaki M., Ishida Y., Kawaichi M., Honjo T. Structure and chromosomal localization of the human PD-1 gene (PDCD1) // Genomics. 1994. V. 23. № 3. P. 704-706.
28. Xiao Y., Yu S., Zhu B., Bedoret D., Bu X., Francisco L.M., Hua P., Duke-Cohan J.S., Umetsu D.T., Sharpe A.H., DeKruyff R.H., Freeman G.J. RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance // J. Exp. Med. 2014. V. 211. № 5. P. 943-959.
29. Schildberg F.A., Klein S.R., Freeman G.J., Sharpe A.H. Coinhibitory pathways in the B7-CD28 ligand-receptor family // Immunity. 2016. Vol. 44. № 5. P. 955-972.
30. Zhu X., Lang J. Soluble PD-1 and PD-L1: predictive and prognostic significance in cancer // Oncotarget. 2017. V. 8. № 57.  P. 97671-97682.
31. Nielsen C., Ohm-Laursen L., Barington T., Husby S., Lillevang S.T. Alternative splice variants of the human PD-1 gene // Cell Immunol. 2005. V. 235. № 2. P. 109-116.
32. Bardhan K., Weaver J., Strauss L., Patsoukis N., Boussiotis V. Phosphorylation of Y248 in the ITSM of PD-1 is indicative of PD-1mediated inhibitory function // J. Immunol. 2017. V. 198. Suppl. 1. P. 154.9.
33. Dong Y., Sun Q., Zhang X. PD-1 and its ligands are important immune checkpoints in cancer // Oncotarget. 2016. Vol. 8. № 2.  P. 2171-2186.
34. Yao S., Chen L. PD-1 as an immune modulatory receptor // Cancer J. 2014. V. 20. № 4. P. 262-264.
35. Chen Y., Wang Q., Shi B., Xu P., Hu Z., Bai L., Zhang X. Development of a sandwich ELISA for evaluating soluble PD-L1 (CD274) in human sera of different ages as well as supernatants of PD-L1+ cell lines // Cytokine. 2011. V. 56. № 2. P. 231-238.
36. He X.H., Xu L.H., Liu Y. Identification of a novel splice variant of human PD-L1 mRNA encoding an isoform-lacking Igv-like domain // Acta Pharmacol. Sin. 2005. V. 26. № 4. P. 462-468.
37. Barber D.L., Wherry E.J., Masopust D., Zhu B., Allison J.P., Sharpe A.H., Freeman G.J., Ahmed R. Restoring function in exhausted CD8 T cells during chronic viral infection // Nature. 2006. V. 439. № 7077. P. 682-687.
38. Crawford A., Angelosanto J.M., Kao C., Doering T.A., Odorizzi P.M., Barnett B.E., Wherry E.J. Molecular and transcriptional basis of CD4⁺ T cell dysfunction during chronic infection // Immunity. 2014. V. 40. № 2. P. 289-302.
39. Pauken K.E., Sammons M.A., Odorizzi P.M., Manne S., Godec J., Khan O., Drake A.M., Chen Z., Sen D.R., Kurachi M., Barnitz R.A., Bartman C., Bengsch B., Huang A.C., Schenkel J.M., Vahedi G., Haining W.N., Berger S.L., Wherry E.J. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade // Science. 2016. V. 354. № 6316. P. 1160-1165.
40. Sen D.R., Kaminski J., Barnitz R.A., Kurachi M., Gerdemann U., Yates K.B., Tsao H.W., Godec J., LaFleur M.W., Brown F.D., Tonnerre P., Chung R.T., Tully D.C., Allen T.M., Frahm N., Lauer G.M., Wherry E.J., Yosef N., Haining W.N. The epigenetic landscape of T cell exhaustion // Science. 2016. V. 354. № 6316. P. 1165-1169.
41. Patsoukis N., Bardhan K., Chatterjee P., Sari D., Liu B., Bell L.N., Karoly E.D., Freeman G.J., Petkova V., Seth P., Li L., Boussiotis V.A. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation // Nat. Commun. 2015. V. 6. P. 6692.
42. Bengsch B., Johnson A.L., Kurachi M., Odorizzi P.M., Pauken K.E., Attanasio J., Stelekati E., McLane L.M., Paley M.A., Delgoffe G.M., Wherry E.J. Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion // Immunity. 2016. V. 45. № 2. P. 358-373.
43. Scharping N.E., Menk A.V., Moreci R.S., Whetstone R.D., Dadey R.E., Watkins S.C., Ferris R.L., Delgoffe G.M. The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction // Immunity. 2016. V. 45. № 3. P. 701-703.
44. Garcia-Diaz A., Shin D.S., Moreno B.H., Saco J., Escuin-Ordinas H., Rodriguez G.A., Zaretsky J.M., Sun L., Hugo W., Wang X., Parisi G., Saus C.P., Torrejon D.Y., Graeber T.G., Comin-Anduix B., Hu-Lieskovan S., Damoiseaux R., Lo R.S., Ribas A. Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression // Cell Rep. 2017. V. 19. № 6. P. 1189-1201.
45. Mimura K., Teh J.L., Okayama H., Shiraishi K., Kua L.F., Koh V., Smoot D.T., Ashktorab H., Oike T., Suzuki Y., Fazreen Z., Asuncion B.R., Shabbir A., Yong W.P., So J., Soong R., Kono K. PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer // Cancer Sci. 2018. V. 109. № 1. P. 43-53.
46. Thibult M.L., Mamessier E., Gertner-Dardenne J., Pastor S., Just-Landi S., Xerri L., Chetaille B., Olive D. PD-1 is a novel regulator of human B-cell activation // Int. Immunol. 2013. V. 25. № 2. P. 129-137.
47. Lin J., Weiss A. T cell receptor signaling // J. Cell. Sci. 2001;114(Pt2):243-244.
48. Yokosuka T., Takamatsu M., Kobayashi-Imanishi W., Hashimoto-Tane A., Azuma M., Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2 // J. Exp. Med. 2012. V. 209. № 6. P. 1201-1217.
49. Horita S., Nomura Y., Sato Y., Shimamura T., Iwata S., Nomura N. High-resolution crystal structure of the therapeutic antibody pembrolizumab bound to the human PD-1 // Sci. Rep. 2016. V. 6. P. 35297.
50. Peled M., Tocheva A.S., Sandigursky S., Nayak S., Philips E.A., Nichols K.E., Strazza M., Azoulay-Alfaguter I., Askenazi M., Neel B.G., Pelzek A.J., Ueberheide B., Mor A. Affinity purification mass spectrometry analysis of PD-1 uncovers SAP as a new checkpoint inhibitor // Proc. Natl. Acad. Sci. U S A. 2018. V. 115. № 3. P. 468-477.
51. Sharpe A.H., Pauken K.E. The diverse functions of the PD1 inhibitory pathway // Nat. Rev. Immunol. 2018. V. 18. № 3. P. 153-167.
52. Okazaki T., Maeda A., Nishimura H., Kurosaki T., Honjo T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine // Proc. Natl. Acad. Sci. U S A. 2001. V. 98.  № 24. P. 13866-13871.
53. Ключагина Ю.И., Соколова З.А., Барышникова М.А. Роль рецептора PD1 и его лигандов PDL1 и PDL2 в иммунотерапии опухолей // Онкопедиатрия. 2017. Т. 4. № 1. С. 49-55
54. Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy // Nat. Rev. Cancer. 2012. V. 12. № 4. P. 252-264.
55. Patel S.P., Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy // Mol. Cancer Ther. 2015. V. 14. № 4.  P. 847-856.
56. Topalian S.L., Taube J.M., Anders R.A., Pardol D.M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy // Nat. Rev. Cancer. 2016. V. 16. № 5. P. 275–287.
57. Gainor J.F., Sequist L.V., Shaw A.T., Azzoli C.G., Piotrowska Z., Huynh T., Fulton L., Schultz K., Hata A.N, Engelman G.A., MinoKenudson M. Clinical correlation and frequency of programmed death ligand-1 (PD-L1) expression in EGFR-mutant and ALKrearranged non-small cell lung cancer (NSCLC) // J. Clin. Oncol. 2015; 33 [suppl.; abstr. 8012].
58. Bhattacharyya T., Purushothaman K., Puthiyottil S.S., Bhattacharjee A., Muttah G. Immunological interactions in radiotherapy– opening a new window of opportunity // Ann. Transl. Med. 2016. V. 4. № 3. P. 51.
59. Qu Q.-X., Xie F., Huang Q., Zhang X.-G. Membranous and Cytoplasmic Expression of PD-L1 in Ovarian Cancer Cells // Cell Physiol. Biochem. 2017. V. 43. P. 1893-1906.
60. Müller M.F., Ibrahim A.E., Arends M.J. Molecular pathological classification of colorectal cancer // Virchows Arch. 2016. V. 469.  № 2. P. 125-134.
61. Shiraliyeva N., Friedrichs J., Buettner R., Friedrichs N. PD-L1 expression in HNPCC-associated colorectal cancer // Pathol. Res. Pract. 2017. V. 213. № 12. P. 1552-1555.
62. Kim J.H., Park H.E., Cho N.Y., Lee H.S., Kang G.H. Characterisation of PD-L1-positive subsets of microsatellite-unstable colorectal cancers // Br. J. Cancer. 2016. V. 115. № 4. P. 490-496.
63. Lee L.H., Cavalcanti M.S., Segal N.H., Hechtman J.F., Weiser M.R., Smith J.J., Garcia-Aguilar J., Sadot E., Ntiamoah P., Markowitz A.J., Shike M., Stadler Z.K., Vakiani E., Klimstra D.S., Shia J. Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma // Mod. Pathol. 2016. V. 29. № 11. P. 1433-1442.
64. Ho H.L., Chou T.Y., Yang S.H., Jiang J.K., Chen W.S., Chao Y., Teng H.W. PD-L1 is a double-edged sword in colorectal cancer: the prognostic value of PD-L1 depends on the cell type expressing PD-L1 // J. Cancer Res. Clin. Oncol. 2019. V. 145. № 7. P. 1785-1794.
65. Lim Y.J., Koh J., Kim S., Jeon S.R., Chie E.K., Kim K. Chemoradiation-Induced Alteration of Programmed Death-Ligand 1 and CD8(+) Tumor-Infiltrating Lymphocytes Identified Patients With Poor Prognosis in Rectal Cancer: A Matched Comparison Analysis // Int. J. Radiat. Oncol. Biol. Phys. 2017. V. 99. № 5. P. 1216–1224.
66. Ogura A., Akiyoshi T., Yamamoto N., Kawachi H., Ishikawa Y., Mori S. Pattern of programmed cell death-ligand 1 expression and CD8-positive T-cell infiltration before and after chemoradiotherapy in rectal cancer // Eur. J. Cancer. 2018. V. 91. P. 11–20.
67. Wyss J., Dislich B., Koelzer V.H., Galván J.A., Dawson H., Hädrich M., Inderbitzin D., Lugli A., Zlobec I., Berger M.D. Stromal PD-1/PD-L1 Expression Predicts Outcome in Colon Cancer Patients // Clin. Colorectal Cancer. 2019. V. 18. № 1. P. 20-38.
68. Elfishawy M., Abd-ELaziz S.A., Hegazy A., El-Yasergy D.F. Immunohistochemical Expression of Programmed Death Ligand-1 (PDL-1) in Colorectal carcinoma and Its Correlation with Stromal Tumor Infiltrating Lymphocytes // Asian Pac. J. Cancer Prev. 2020. V. 21. № 1. P. 225-232.
69. Zhong G., Peng C., Chen Y., Li J., Yang R., Wu M., Lu P. Expression of STING and PD-L1 in colorectal cancer and their correlation with clinical prognosis // Int. J. Clin. Exp. Pathol. 2018. V. 11. № 3. P. 1256-1264.
70. Droeser R.A., Hirt C., Viehl C.T., Frey D.M., Nebiker C., Huber X., Zlobec I., Eppenberger-Castori S., Tzankov A., Rosso R., Zuber M., Muraro M.G., Amicarella F., Cremonesi E., Heberer M., Iezzi G., Lugli A., Terracciano L., Sconocchia G., Oertli D., Spagnoli G.C., Tornillo L. Clinical impact of programmed cell death ligand 1 expression in colorectal cancer // Eur. J. Cancer. 2013. V. 49. № 9.  P. 2233-2242.
71. Inaguma S., Lasota J., Wang Z., Felisiak-Golabek A., Ikeda H., Miettinen M. Clinicopathologic profile, immunophenotype, and genotype of CD274 (PD-L1)-positive colorectal carcinomas // Mod. Pathol. 2017. V. 30. № 2. P. 278-285.
72. El Jabbour T., Ross J.S., Sheehan C.E., Affolter K.E., Geiersbach K.B., Boguniewicz A., Ainechi S., Bronner M.P., Jones D.M., Lee H. PD-L1 protein expression in tumour cells and immune cells in mismatch repair protein-deficient and –proficient colorectal cancer: the foundation study using the SP142 antibody and whole section immunohistochemistry // J. Clin. Pathol. 2018. V. 71. № 1. P. 46-51.
73. Lee K.S. et al. Prognostic implication of CD274 (PD-L1) protein expression in tumor-infiltrating immune cells for microsatellite unstable and stable colorectal cancer // Cancer Immunol. Immunother. 2017. V. 66. P. 927-939.
74. Wang H.B., Yao H., Li C.S., Liang L.X., Zhang Y., Chen Y.X., Fang J.Y., Xu J. Rise of PD-L1 expression during metastasis of colorectal cancer: Implications for immunotherapy // J. Dig. Dis. 2017. V. 18. № 10. P. 574-581.
75. Sasidharan Nair V., Toor S.M., Taha R.Z., Shaath H., Elkord E. DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer // Clin. Epigenetics. 2018. V. 10. № 1. P. 104.
76. Kim H.J., Park S., Kim K.J., Seong J. Clinical significance of soluble programmed cell death ligand-1 (sPD-L1) in hepatocellular carcinoma patients treated with radiotherapy // Radiother. Oncol. 2018. V. 129. № 1. P. 130-135.
77. Theodoraki M.N., Yerneni S.S., Hoffmann T.K., Gooding W.E., Whiteside T.L. Clinical Significance of PD-L1+ Exosomes in Plasma of Head and Neck Cancer Patients // Clin. Cancer Res. 2018. V. 24. № 4. P. 896-905.
78. Tominaga T., Akiyoshi T., Yamamoto N., Taguchi S., Mori S., Nagasaki T., Fukunaga Y., Ueno M. Clinical significance of soluble programmed cell death-1 and soluble programmed cell death-ligand 1 in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy // PLoS One. 2019. V. 14. № 2. P. 0212978.
79. Muneoka K., Shirai Y., Sasaki M., Honma S., Sakata J., Kanda J., Wakabayashi H., Wakai T., Miyazaki M. Selection of Chemotherapy Regimen on the Basis of Monitoring NLR and Soluble PD-L1 during CRC Chemotherapy // Gan To Kagaku Ryoho. 2018. V. 45.  № 8. P. 1159-1163.
80. Shoji S., Nakano M., Sato H., Tang X.Y., Osamura Y.R., Terachi T., Uchida T., Takeya K. The current status of tailor-made medicine with molecular biomarkers for patients with clear cell renal cell carcinoma // Clin. Exp. Metastasis. 2014. V. 31. № 1. P. 111-134.
81. Dizon D.S., Krilov L., Cohen E., Gangadhar T., Ganz P.A., Hensing T.A., Hunger S., Krishnamurthi S.S., Lassman A.B., Markham M.J., Mayer E, Neuss M., Pal S.K., Richardson L, Schilsky R., Schwartz G.K., Spriggs D.R., Villalona-Calero M.A., Villani G., Masters G. Clinical Cancer Advances 2016: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology // J. Clin. Oncol. 2016. V. 34. № 9. P. 987-1011.
82. Barata P.C., Rini B.I. Treatment of renal cell carcinoma: Current status and future directions // CA Cancer J. Clin. 2017. V. 67.  № 6. P. 507-524.
83. Liu K.G., Gupta S., Goel S. Immunotherapy: incorporation in the evolving paradigm of renal cancer management and future prospects // Oncotarget. 2017. V. 8. № 10. P. 17313-17327.
84. Taube J.M., Klein A., Brahmer J.R., Xu H., Pan X., Kim J.H., Chen L., Pardoll D.M., Topalian S.L., Anders R.A. 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. V. 20. № 19. P. 5064-5074.
85. Cantero-Cid R., Casas-Martin J., Hernández-Jiménez E., Cubillos-Zapata C., Varela-Serrano A., Avendaño-Ortiz J., Casarrubios M., Montalbán-Hernández K., Villacañas-Gil I., Guerra-Pastrián L., Peinado B., Marcano C., Aguirre L.A., López-Collazo E. PDL1/PD-1 crosstalk in colorectal cancer: are we targeting the right cells? // BMC Cancer. 2018. V. 18. № 1. P. 945.
86. Arai Y., Saito H., Ikeguchi M. Upregulation of TIM-3 and PD-1 on CD4+ and CD8+ T Cells Associated with Dysfunction of CellMediated Immunity after Colorectal Cancer Operation // Yonago Acta Med. 2012. V. 55. P. 1-9.
87. Le D.T., Uram J.N., Wang H., Bartlett B.R., Kemberling H., Eyring A.D., Skora A.D., Luber B.S., Azad N.S., Laheru D., Biedrzycki B., Donehower R.C., Zaheer A., Fisher G.A., Crocenzi T.S., Lee J.J., Duffy S.M., Gold-berg R.M., de la Chapelle A., Koshiji M., Bhaijee F., Huebner T., Hruban R.H., Wood L.D., Cuka N., Pardoll D.M., Papadopoulos N., Kinzler K.W., Zhou S., Cornish T.C., Taube J.M.,  Anders R.A., Eshleman J.R., Vogelstein B., Diaz L.A. Jr. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency // N. Engl. J. Med. 2015. V. 372. № 26. P. 2509-2520.
88. Tumeh P.C., Harview C.L., Yearley J.H., Shintaku I.P., Taylor E.J., Robert L., Chmielowski B., Spasic M., Henry G., Ciobanu V.,  West A.N., Carmona M., Kivork C., Seja E., Cherry G., Gutierrez A.J., Grogan T.R., Mateus C., Tomasic G., Glaspy J.A., Emerson R.O., Robins H., Pierce R.H., Elashoff D.A., Robert C., Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance // Nature. 2014. V. 515. № 7528. P. 568-571.
89. Madore J., Vilain R.E., Menzies A.M., Kakavand H., Wilmott J.S., Hyman J., Yearley J.H., Kefford R.F., Thompson J.F., Long G.V., Hersey P., Scolyer R.A. PD-L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti-PD-1/PD-L1 clinical trials // Pigment Cell Melanoma Res. 2015. V. 28. № 3. P. 245-253.
90. Yi J.S., Cox M.A., Zajac A.J. T-cell exhaustion: characteristics, causes and conversion // Immunology. 2010. V. 129. № 4. P. 474–481.
91. Zhang Y., Zhu W., Zhang X., Qu Q., Zhang L. Expression and clinical significance of programmed death-1 on lymphocytes and programmed death ligand-1 on monocytes in the peripheral blood of patients with cervical cancer // Oncol. Lett. 2017. V. 14. № 6.  P. 7225-7231.
92. Overman M.J., Lonardi S., Wong K.Y.M., Lenz H.J., Gelsomino F., Aglietta M., Morse M.A., Van Cutsem E., McDermott R., Hill A., Sawyer M.B., Hendlisz A., Neyns B., Svrcek M., Moss R.A., Ledeine J.M., Cao Z.A., Kamble S., Kopetz S., André T. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer // J. Clin. Oncol. 2018. V. 36. № 8. P. 773-779.
93. Dosset M., Vargas T.R., Lagrange A., Boidot R., Végran F., Roussey A., Chalmin F., Dondaine L., Paul C., Lauret Marie-Joseph E., Martin F., Ryffel B., Borg C, Adotévi O., Ghiringhelli F., Apetoh L. PD-1/PD-L1 pathway: an adaptive immune resistance mechanism to immunogenic chemotherapy in colorectal cancer // Oncoimmunology. 2018. V. 7. № 6. e1433981.
94. Weber M.M., Fottner C. Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia // Oncol. Res. Treat. 2018. V. 41. № 5. P. 306-312.
95. Камышов С.В. Механизмы иммунных нарушений у пациентов с раком яичников, получавших химиотерапию, и их динамика на фоне иммунотерапии // Евразийский онкологический журнал. 2018. Т. 6. № 2. C. 563-565.
96. Wieser V., Gaugg I., Fleischer M., Shivalingaiah G., Wenzel S., Sprung S., Lax S.F., Zeimet A.G., Fiegl H., Marth C. BRCA1/2 and TP53 mutation status associates with PD-1 and PD-L1 expression in ovarian cancer // Oncotarget. 2018. V. 9. № 25. P. 17501-17511.
97. Demaria S., Coleman C.N., Formenti S.C. Radiotherapy: Changing the Game in Immunotherapy // Trends in Cancer. 2016. V. 2.  Iss. 6. P. 286-294.
98. Seyedin S.N., Hasibuzzaman M.M., Pham V., Petronek M.S., Callaghan C., Kalen A.L., Mapuskar K.A., Mott S.L., Spitz D.R., Allen B.G., Caster J.M. Combination Therapy With Radiation and PARP Inhibition Enhances Responsiveness to Anti-PD-1 Therapy in Colorectal Tumor Models // Int. J. Radiat. Oncol. Biol. Phys. 2020. V. 108. № 1. P. 81-92.
99. Wahba J., Natoli M., Whilding L.M., Parente-Pereira A.C., Jung Y., Zona S., Lam E.W., Smith J.R., Maher J., Ghaem-Maghami S. Chemotherapy-induced apoptosis, autophagy and cell cycle arrest are key drivers of synergy in chemo-immunotherapy of epithelial ovarian cancer // Cancer Immunol. Immunother. 2018. Aug 24. doi: 10.1007/s00262-018-2199-8 [Epub ahead of print].
100. Ngwa W., Irabor O.C., Schoenfeld J.D., Hesser J., Demaria S., Formenti S.C. Using Immunotherapy to Boost the Abscopal Effect // Nat. Rev. Cancer. 2018. V. 18. № 5. P. 313-322.