medalphabetМедицинский алфавитMedical alphabet2078-56312949-2807ООО «Альфмед»10.33667/2078-5631-2021-41-41-46medalphabet-2421Research ArticleОБОЗРЕНИЕREVIEWБиомаркеры опухолевого микроокружения злокачественных новообразований почек, мочевого пузыря, предстательной железы (обзор литературы)Biomarkers of tumor microenvironment of malignant neoplasms of kidneys, urinary bladder, and prostate gland (literature review)https://orcid.org/0000-0001-9410-2240ЗахароваН. Б.ZakharovaN. B.

Захарова Наталия Борисовна, д.м.н., профессор кафедры клинической лабораторной диагностикиSPIN: 5354–6327AuthorID: 712752

Саратов

Zakharova Natalia B., DM Sci (habil.), professor at Dept of Clinical Laboratory DiagnosticsSPIN: 5354–6327AuthorID: 712752. 

Saratov

lipidgormon@mail.ruhttps://orcid.org/0000-0003-2547-5654ПонукалинА. Н.PonukalinA. N.

Понукалин Андрей Николаевич, к.м.н., доцент кафедры урологии. SPIN: 9825–6425AuthorID: 412895

Саратов

Ponukalin Andrey N., PhD Med, associate professor at Dept of UrologySPIN: 9825–6425AuthorID: 412895

Saratov

https://orcid.org/0000-0003-4507-9456ЧехонацкаяМ. Л.ChekhonatskayaM. L.

Чехонацкая Марина Леонидовна, д.м.н., зав. кафедрой лучевой диагностики и лучевой терапии им. профессора Н.Е. ШтернаSPIN: 7574–3230AuthorID: 502866

Саратов

Chekhonatskaya Marina L., DM Sci (habil.), head of Dept of Radiation Diagnostics and Radiation Therapy n.a. professor N.E. SternSPIN: 7574–3230AuthorID: 502866

Saratov

КоролевА. Ю.KorolevA. Y.

Королев Александр Юрьевич, к.м.н., ассистент кафедры урологииSPIN: 7633–9250AuthorID: 715000

Саратов

Korolev Alexander Yu., PhD Med, assistant at Dept of UrologySPIN: 7633–9250AuthorID: 715000

Saratov

https://orcid.org/0000-0001-7603-1012КомягинаЮ. М.KomyaginaY. M.

Комягина Юлия Михайловна, соискатель кафедры урологии SPIN: 2595–1354

Саратов

Komyagina Yulia M., applicant at Dept of UrologySPIN: 2595–1354

Saratov

ФГБОУ ВО «Саратовский государственный медицинский университет имени В.И. Разумовского» Минздрава РоссииРоссияSaratov State Medical University n.a. V.I. RazumovskyRussian Federation202110012022041Обозрение (1)4146Copyright © Захарова Н.Б., Понукалин А.Н., Чехонацкая М.Л., Королев А.Ю., Комягина Ю.М., 20222022Захарова Н.Б., Понукалин А.Н., Чехонацкая М.Л., Королев А.Ю., Комягина Ю.М.Zakharova N.B., Ponukalin A.N., Chekhonatskaya M.L., Korolev A.Y., Komyagina Y.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-alphabet.com/jour/article/view/2421

Развитие злокачественной трансформации ткани сопровождается накоплением в ней клеток иммунной системы или клеток опухолевого микроокружения (МкО). Выделено три варианта накопления иммунных клеток: «иммуннопустынный» фенотип, «горячие» опухоли, с цитолитическим Т-клеточным ответом. В обзоре представлены иммунотерапевтические стратегии воздействия с целью усиления способности МкО инициировать иммунные механизмы, способные блокировать развитие опухолевой ткани. Проведен анализ представленных данных о значении иммуноонкологических биомаркеров в качестве лабораторных показателей терапевтической эффективности лекарственной терапии, направленной на восстановление ключевых иммунных путей защиты при онкоурологических заболеваниях. Обобщены результаты исследования эффективности иммуноонкологических биомаркеров для оценки состояния противоопухолевого иммунитета при злокачественных новообразованиях мочевого пузыря, почек, предстательной железы.

The development of malignant tissue transformation is accompanied by the accumulation of immune system cells or tumor microenvironment cells (MCO) in it. Three variants of immune cell accumulation were identified: the ‘immune desert’ phenotype, ‘hot’ tumors, with a cytolytic T-cell response. The review presents immunotherapeutic strategies of exposure in order to enhance the ability of McO to initiate immune mechanisms capable of blocking the development of tumor tissue. The analysis of the presented data on the importance of immuno-oncological biomarkers as laboratory indicators of the therapeutic effectiveness of drug therapy aimed at restoring key immune defense pathways in oncourological diseases was carried out. The results of the study of the effectiveness of immuno-oncological biomarkers for assessing the state of antitumor immunity in malignant neoplasms of the bladder, kidneys, prostate gland are summarized.

иммунотерапиябиомаркерырак почкирак мочевого пузырярак предстательной железымедиаторы микроокружения опухолиметастазированиеkidney cancerbladder cancerprostate cancertumor microenvironment mediatorsmetastasisReferencesMartins F, Sykiotis GP, Maillard M, Fraga M, Ribi C, Kuntzer T, Michielin O, Peters S, Coukos G, Spertini F, Thompson JA, Obeid M. New therapeutic perspectives to manage refractory immune checkpoint-related toxicities. Lancet Oncol. 2019; 20 (1): e54–e64. DOI:10.1016/S1470–2045(18)30828–3. PMID: 30614479.Martins F, Sykiotis GP, Maillard M, Fraga M, Ribi C, Kuntzer T, Michielin O, Peters S, Coukos G, Spertini F, Thompson JA, Obeid M. New therapeutic perspectives to manage refractory immune checkpoint-related toxicities. Lancet Oncol. 2019; 20 (1): e54–e64. DOI:10.1016/S1470–2045(18)30828–3. PMID: 30614479.Gnjatic S., Bronte V., Brunet L.R. et al. Identifying baseline immune-related biomarkers to predict clinical outcome of immunotherapy. J. Immunotherapy Cancer 5, 44 (2017). https://doi.org/10.1186/s40425–017–0243–4Gnjatic S., Bronte V., Brunet L.R. et al. Identifying baseline immune-related biomarkers to predict clinical outcome of immunotherapy. J. Immunotherapy Cancer 5, 44 (2017). https://doi.org/10.1186/s40425–017–0243–4Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol. 2017; 17 (9): 559–572. DOI:10.1038/nri.2017.49. Epub 2017 May 30. PMID:28555670; PMCID: PMC5731833.Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol. 2017; 17 (9): 559–572. DOI:10.1038/nri.2017.49. Epub 2017 May 30. PMID:28555670; PMCID: PMC5731833.Yun C.W., Lee S.H. The Roles of Autophagy in Cancer. Int. J. Mol. Sci. 2018; 19 (11): 3466. DOI:10.3390/ijms19113466.Yun C.W., Lee S.H. The Roles of Autophagy in Cancer. Int. J. Mol. Sci. 2018; 19 (11): 3466. DOI:10.3390/ijms19113466.Binnewies M., Roberts E.W., Kersten K., Chan V., Fearon D. F., Merad M., et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 2018; 24 (5): 541–550. DOI:10.1038/s41591–018–0014-xBinnewies M., Roberts E.W., Kersten K., Chan V., Fearon D. F., Merad M., et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 2018; 24 (5): 541–550. DOI:10.1038/s41591–018–0014-xHernandez C., Huebener P., Schwabe R. F. Damage-associated molecular patterns in cancer: a double-edged sword. Oncogene. 2016; 35 (46): 5931–5941. DOI:10.1038/onc.2016.104.Hernandez C., Huebener P., Schwabe R. F. Damage-associated molecular patterns in cancer: a double-edged sword. Oncogene. 2016; 35 (46): 5931–5941. DOI:10.1038/onc.2016.104.Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017; 541 (7637): 321–330. DOI:10.1038/nature21349. PMID:28102259.Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017; 541 (7637): 321–330. DOI:10.1038/nature21349. PMID:28102259.Wilkinson RW, Leishman AJ. Further Advances in Cancer Immunotherapy: Going Beyond Checkpoint Blockade. Front. Immunol. 2018; 9: 1082. DOI:10.3389/fimmu.2018.01082.Wilkinson RW, Leishman AJ. Further Advances in Cancer Immunotherapy: Going Beyond Checkpoint Blockade. Front. Immunol. 2018; 9: 1082. DOI:10.3389/fimmu.2018.01082.Wei S. C., Duff C. R., Allison J. P. Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Cancer Discovery. 2018; 8 (9): 1069–1086. DOI:10.1158/2159–8290.CD‑18–0367.Wei S. C., Duff C. R., Allison J. P. Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Cancer Discovery. 2018; 8 (9): 1069–1086. DOI:10.1158/2159–8290.CD‑18–0367.Buchbinder EI, Desai A. CTLA‑4 and PD‑1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016; 39 (1): 98–106. DOI:10.1097/COC.0000000000000239.Buchbinder EI, Desai A. CTLA‑4 and PD‑1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016; 39 (1): 98–106. DOI:10.1097/COC.0000000000000239.Eroglu Z, Zaretsky JM, Hu-Lieskovan S, Kim DW, Algazi A, Johnson DB, Liniker E, Ben Kong, Munhoz R, Rapisuwon S, Gherardini PF, Chmielowski B, Wang X, Shintaku IP, Wei C, Sosman JA, Joseph RW, Postow MA, Carlino MS, Hwu WJ, Scolyer RA, Messina J, Cochran AJ, Long GV, Ribas A. High response rate to PD‑1 blockade in desmoplastic melanomas. Nature. 2018; 553 (7688): 347–350. DOI:10.1038/nature25187. Epub 2018 Jan 10. PMID:29320474; PMCID: PMC5773412.Eroglu Z, Zaretsky JM, Hu-Lieskovan S, Kim DW, Algazi A, Johnson DB, Liniker E, Ben Kong, Munhoz R, Rapisuwon S, Gherardini PF, Chmielowski B, Wang X, Shintaku IP, Wei C, Sosman JA, Joseph RW, Postow MA, Carlino MS, Hwu WJ, Scolyer RA, Messina J, Cochran AJ, Long GV, Ribas A. High response rate to PD‑1 blockade in desmoplastic melanomas. Nature. 2018; 553 (7688): 347–350. DOI:10.1038/nature25187. Epub 2018 Jan 10. PMID:29320474; PMCID: PMC5773412.Tarhini A. Immune-mediated adverse events associated with ipilimumab CTLA‑4 blockade therapy: the underlying mechanisms and clinical management. Scientifica (Cairo). 2013; 2013: 857519. https://doi.org/10.1155/2013/857519.Tarhini A. Immune-mediated adverse events associated with ipilimumab CTLA‑4 blockade therapy: the underlying mechanisms and clinical management. Scientifica (Cairo). 2013; 2013: 857519. https://doi.org/10.1155/2013/857519.Champiat S., Dercle L., Ammari S., Massard Ch., Hollebecque A., Postel-Vinay S., Chaput N., Eggermont A., Marabelle A., Soria J.-Ch., Ferté Ch. Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD‑1/PD-L1. Clin Cancer Res. 2017; (23) (8): 1920–1928. DOI:10.1158/1078–0432.CCR‑16–1741.Champiat S., Dercle L., Ammari S., Massard Ch., Hollebecque A., Postel-Vinay S., Chaput N., Eggermont A., Marabelle A., Soria J.-Ch., Ferté Ch. Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD‑1/PD-L1. Clin Cancer Res. 2017; (23) (8): 1920–1928. DOI:10.1158/1078–0432.CCR‑16–1741.Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P, Chandra AB. Current Diagnosis and Management of Immune Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitor Therapy. Front Pharmacol. 2017; 8: 49. DOI:10.3389/fphar.2017.00049.Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P, Chandra AB. Current Diagnosis and Management of Immune Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitor Therapy. Front Pharmacol. 2017; 8: 49. DOI:10.3389/fphar.2017.00049.Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, Berdelou A, Varga A, Bahleda R, Hollebecque A, Massard C, Fuerea A, Ribrag V, Gazzah A, Armand JP, Amellal N, Angevin E, Noel N, Boutros C, Mateus C, Robert C, Soria JC, Marabelle A, Lambotte O. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016; 54: 139–148. DOI:10.1016/j.ejca.2015.11.016.Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, Berdelou A, Varga A, Bahleda R, Hollebecque A, Massard C, Fuerea A, Ribrag V, Gazzah A, Armand JP, Amellal N, Angevin E, Noel N, Boutros C, Mateus C, Robert C, Soria JC, Marabelle A, Lambotte O. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016; 54: 139–148. DOI:10.1016/j.ejca.2015.11.016.Pearson AT, Sweis RF. Hyperprogression-Immunotherapy-Related Phenomenon vs Intrinsic Natural History of Cancer. JAMA Oncol. 2019; 5 (5): 743. DOI:10.1001/jamaoncol.2019.0130.Pearson AT, Sweis RF. Hyperprogression-Immunotherapy-Related Phenomenon vs Intrinsic Natural History of Cancer. JAMA Oncol. 2019; 5 (5): 743. DOI:10.1001/jamaoncol.2019.0130.Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA. Cancer immunology. Mutational landscape determines sensitivity to PD‑1 blockade in non-small cell lung cancer. Science. 2015; 348 (6230): 124–8. DOI:10.1126/science.aaa1348.Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA. Cancer immunology. Mutational landscape determines sensitivity to PD‑1 blockade in non-small cell lung cancer. Science. 2015; 348 (6230): 124–8. DOI:10.1126/science.aaa1348.Najafi M, Goradel NH, Farhood B, Salehi E, Solhjoo S, Toolee H, et al. Tumor microenvironment: interactions and therapy. J Cell Physiol. 2019; 234: 5700–21. DOI:10.1002/jcp.27425.Najafi M, Goradel NH, Farhood B, Salehi E, Solhjoo S, Toolee H, et al. Tumor microenvironment: interactions and therapy. J Cell Physiol. 2019; 234: 5700–21. DOI:10.1002/jcp.27425.Chen D. S., Mellman I. Elements of cancer immunity and the cancer–immune set point. Nature 2017; 7637 (541): 321–330.Chen D. S., Mellman I. Elements of cancer immunity and the cancer–immune set point. Nature 2017; 7637 (541): 321–330.Garg A.D., Vara Perez M., Schaaf M., Agostinis P., Zitvogel L., Kroemer G., Galluzzi L. Trial watch: Dendritic cell-based anticancer immunotherapy. Oncoimmunology. 2017; 6: e1328341. DOI:10.1080/2162402X.2017.1328341.Garg A.D., Vara Perez M., Schaaf M., Agostinis P., Zitvogel L., Kroemer G., Galluzzi L. Trial watch: Dendritic cell-based anticancer immunotherapy. Oncoimmunology. 2017; 6: e1328341. DOI:10.1080/2162402X.2017.1328341.Anguille S., Smits E. L., Lion E., van Tendeloo V. F., Berneman Z. N. Clinical use of dendritic cells for cancer therapy. The Lancet. Oncology 2014; 15: e257–267, DOI:10.1016/S1470–2045(13)70585–0.Anguille S., Smits E. L., Lion E., van Tendeloo V. F., Berneman Z. N. Clinical use of dendritic cells for cancer therapy. The Lancet. Oncology 2014; 15: e257–267, DOI:10.1016/S1470–2045(13)70585–0.Christofi T.; Baritaki S.; Falzone L.; Libra M.; Zaravinos A. Current Perspectives in Cancer Immunotherapy. Cancers (Basel) 2019; 11: DOI:10.3390/cancers11101472.Christofi T.; Baritaki S.; Falzone L.; Libra M.; Zaravinos A. Current Perspectives in Cancer Immunotherapy. Cancers (Basel) 2019; 11: DOI:10.3390/cancers11101472.Rosenberg S. A.; Yang J. C.; Sherry R. M.; Kammula U. S.; Hughes M. S.; Phan G. Q.; Citrin D. E.; Restifo N. P.; Robbins P. F.; Wunderlich J. R., et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clinical cancer research: an official journal of the American Association for Cancer Research 2011, 17, 4550–4557, DOI:10.1158/1078–0432.CCR‑11–0116.Rosenberg S. A.; Yang J. C.; Sherry R. M.; Kammula U. S.; Hughes M. S.; Phan G. Q.; Citrin D. E.; Restifo N. P.; Robbins P. F.; Wunderlich J. R., et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clinical cancer research: an official journal of the American Association for Cancer Research 2011, 17, 4550–4557, DOI:10.1158/1078–0432.CCR‑11–0116.Besser M. J.; Shapira-Frommer R.; Itzhaki O.; Treves A. J.; Zippel D. B.; Levy D.; Kubi A.; Shoshani N.; Zikich D.; Ohayon Y., et al. Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies. Clinical cancer research: an official journal of the American Association for Cancer Research 2013, 19, 4792–4800, DOI:10.1158/1078–0432.CCR‑13–0380.Besser M. J.; Shapira-Frommer R.; Itzhaki O.; Treves A. J.; Zippel D. B.; Levy D.; Kubi A.; Shoshani N.; Zikich D.; Ohayon Y., et al. Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies. Clinical cancer research: an official journal of the American Association for Cancer Research 2013, 19, 4792–4800, DOI:10.1158/1078–0432.CCR‑13–0380.Sukari A.; Abdallah N.; Nagasaka M. Unleash the power of the mighty T cells-basis of adoptive cellular therapy. Crit Rev Oncol Hematol 2019, 136, 1–12, DOI:10.1016/j.critrevonc.2019.01.015.Sukari A.; Abdallah N.; Nagasaka M. Unleash the power of the mighty T cells-basis of adoptive cellular therapy. Crit Rev Oncol Hematol 2019, 136, 1–12, DOI:10.1016/j.critrevonc.2019.01.015.Xia A. L.; Wang X. C.; Lu Y. J.; Lu X. J.; Sun B. Chimeric-antigen receptor T (CAR-T) cell therapy for solid tumors: challenges and opportunities. Oncotarget. 2017; 8: 90521–90531, DOI:10.18632/oncotarget.19361.Xia A. L.; Wang X. C.; Lu Y. J.; Lu X. J.; Sun B. Chimeric-antigen receptor T (CAR-T) cell therapy for solid tumors: challenges and opportunities. Oncotarget. 2017; 8: 90521–90531, DOI:10.18632/oncotarget.19361.Zabel M.; Tauber P. A.; Pickl W. F. The making and function of CAR cells. Immunology letters 2019; 212: 53–69, DOI:10.1016/j.imlet.2019.06.002.Zabel M.; Tauber P. A.; Pickl W. F. The making and function of CAR cells. Immunology letters 2019; 212: 53–69, DOI:10.1016/j.imlet.2019.06.002.Munn DH, Bronte V. Immune suppressive mechanisms in the tumor microenvironment. Curr Opin Immunol. 2016; 39: 1–6. DOI:10.1016/j.coi.2015.10.009.Munn DH, Bronte V. Immune suppressive mechanisms in the tumor microenvironment. Curr Opin Immunol. 2016; 39: 1–6. DOI:10.1016/j.coi.2015.10.009.Correa LH, Correa R, Farinasso CM, de Sant‘Ana Dourado LP, Magalhaes KG. Adipocytes and macrophages interplay in the orchestration of tumor microenvironment: new implications in cancer progression. Front Immunol. 2017; 8: 1129. DOI:10.3389/fimmu.2017.01129.Correa LH, Correa R, Farinasso CM, de Sant‘Ana Dourado LP, Magalhaes KG. Adipocytes and macrophages interplay in the orchestration of tumor microenvironment: new implications in cancer progression. Front Immunol. 2017; 8: 1129. DOI:10.3389/fimmu.2017.01129.Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017; 14 (7): 399–416. DOI:10.1038/nrclinonc.2016.217.Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017; 14 (7): 399–416. DOI:10.1038/nrclinonc.2016.217.Brabletz T., Kalluri R., Nieto M.A., Weinberg R.A. EMT in cancer. Nat. Rev. Cancer. 2018; 18 (2): 128–134. DOI:10.1038/nrc.2017.118.Brabletz T., Kalluri R., Nieto M.A., Weinberg R.A. EMT in cancer. Nat. Rev. Cancer. 2018; 18 (2): 128–134. DOI:10.1038/nrc.2017.118.Sainz B. Jr., Carron E., Vallespinos M., Machado H. L. Cancer Stem Cells and Macrophages: Implications in Tumor Biology and Therapeutic Strategies. Mediators Inflammation 2016; 9012369. DOI:10.1155/2016/9012369.Sainz B. Jr., Carron E., Vallespinos M., Machado H. L. Cancer Stem Cells and Macrophages: Implications in Tumor Biology and Therapeutic Strategies. Mediators Inflammation 2016; 9012369. DOI:10.1155/2016/9012369.Genard G, Lucas S and Michiels C. Reprogramming of Tumor-Associated Macrophages with Anticancer Therapies: Radiotherapy versus Chemo- and Immunotherapies. Front. Immunol. 2017; 8: 828. DOI:10.3389/fimmu.2017.00828.Genard G, Lucas S and Michiels C. Reprogramming of Tumor-Associated Macrophages with Anticancer Therapies: Radiotherapy versus Chemo- and Immunotherapies. Front. Immunol. 2017; 8: 828. DOI:10.3389/fimmu.2017.00828.Yang Q, Guo N, Zhou Y, Chen J, Wei Q, Han M, The role of tumor-associated macrophages (TAMs) in tumor progression and relevant advance in targeted therapy, Acta Pharmaceutica Sinica B 2020; 11 (10): 2156–2170 https://doi.org/10.1016/j.apsb.2020.04.004Yang Q, Guo N, Zhou Y, Chen J, Wei Q, Han M, The role of tumor-associated macrophages (TAMs) in tumor progression and relevant advance in targeted therapy, Acta Pharmaceutica Sinica B 2020; 11 (10): 2156–2170 https://doi.org/10.1016/j.apsb.2020.04.004Komohara Y, Fujiwara Y, Ohnishi K, Takeya M. Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy. Adv Drug Deliv Rev. 2016; 99 (Pt B): 180–185. DOI:10.1016/j.addr.2015.11.009.Komohara Y, Fujiwara Y, Ohnishi K, Takeya M. Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy. Adv Drug Deliv Rev. 2016; 99 (Pt B): 180–185. DOI:10.1016/j.addr.2015.11.009.Sharma P. Immune checkpoint therapy and the search for predictive biomarkers. Cancer J. 2016; 22: 68–72. DOI:10.1097/PPO.0000000000000185.Sharma P. Immune checkpoint therapy and the search for predictive biomarkers. Cancer J. 2016; 22: 68–72. DOI:10.1097/PPO.0000000000000185.Dobbin KK, Cesano A, Alvarez J, Hawtin R, Janetzki S, Kirsch I, Masucci GV, Robbins PB, Selvan SR, Streicher HZ, Zhang J, Butterfield LH, Thurin M. Validation of biomarkers to predict response to immunotherapy in cancer: Volume II – clinical validation and regulatory considerations. J Immunother Cancer. 2016; 4: 77. DOI:10.1186/s40425–016–0179–0.Dobbin KK, Cesano A, Alvarez J, Hawtin R, Janetzki S, Kirsch I, Masucci GV, Robbins PB, Selvan SR, Streicher HZ, Zhang J, Butterfield LH, Thurin M. Validation of biomarkers to predict response to immunotherapy in cancer: Volume II – clinical validation and regulatory considerations. J Immunother Cancer. 2016; 4: 77. DOI:10.1186/s40425–016–0179–0.Komohara Y., Fujiwara Y., Ohnishi K., Takeya M. Tumor–associated macrophages: Potential therapeutic targets for anti–cancer therapy. Advanced Drug Delivery Reviews. 2016; 99: 180–185. DOI:10.1016/j.addr.2015.11.009.Komohara Y., Fujiwara Y., Ohnishi K., Takeya M. Tumor–associated macrophages: Potential therapeutic targets for anti–cancer therapy. Advanced Drug Delivery Reviews. 2016; 99: 180–185. DOI:10.1016/j.addr.2015.11.009.Mantovani A., Allavena P. The interaction of anticancer therapies with tumor–associated macrophages. Journal of Experimental Medicine. 2015; 212 (4): 435–45. DOI:10.1084/jem.20150295.Mantovani A., Allavena P. The interaction of anticancer therapies with tumor–associated macrophages. Journal of Experimental Medicine. 2015; 212 (4): 435–45. DOI:10.1084/jem.20150295.Masucci GV, Cesano A, Hawtin R, Janetzki S, Zhang J, Kirsch I, Dobbin KK, Alvarez J, Robbins PB, Selvan SR, Streicher HZ, Butterfield LH, Thurin M. Validation of biomarkers to predict response to immunotherapy in cancer: Volume I – pre-analytical and analytical validation. J Immunother Cancer. 2016; 4: 76. DOI:10.1186/s40425–016–0178–1.Masucci GV, Cesano A, Hawtin R, Janetzki S, Zhang J, Kirsch I, Dobbin KK, Alvarez J, Robbins PB, Selvan SR, Streicher HZ, Butterfield LH, Thurin M. Validation of biomarkers to predict response to immunotherapy in cancer: Volume I – pre-analytical and analytical validation. J Immunother Cancer. 2016; 4: 76. DOI:10.1186/s40425–016–0178–1.Nixon AB, Schalper KA, Jacobs I, Potluri S, Wang IM, Fleener C. Peripheral immune-based biomarkers in cancer immunotherapy: can we realize their predictive potential? J Immunother Cancer. 2019 Nov 27; 7 (1): 325. DOI:10.1186/s40425–019–0799–2.Nixon AB, Schalper KA, Jacobs I, Potluri S, Wang IM, Fleener C. Peripheral immune-based biomarkers in cancer immunotherapy: can we realize their predictive potential? J Immunother Cancer. 2019 Nov 27; 7 (1): 325. DOI:10.1186/s40425–019–0799–2.Smith H. O., Stephens N. D., Qualls C. R., Fligelman T., Wang T., Lin C. Y., Burton E., Griffith J.K., Pollard J.W. The clinical significance of inflammatory cytokines in primary cell culture in endometrial carcinoma. Mol. Oncol. 2013; 7 (1): 41–54. DOI:10.1016/j.molonc.2012.07.002.Smith H. O., Stephens N. D., Qualls C. R., Fligelman T., Wang T., Lin C. Y., Burton E., Griffith J.K., Pollard J.W. The clinical significance of inflammatory cytokines in primary cell culture in endometrial carcinoma. Mol. Oncol. 2013; 7 (1): 41–54. DOI:10.1016/j.molonc.2012.07.002.Kuwada K, Kagawa S, Yoshida R, Sakamoto S, Ito A, Watanabe M, Ieda T, Kuroda S, Kikuchi S, Tazawa H, Fujiwara T. The epithelial-to-mesenchymal transition induced by tumor-associated macrophages confers chemoresistance in peritoneally disseminated pancreatic cancer. J Exp Clin Cancer Res. 2018; 37 (1): 307. DOI:10.1186/s13046–018–0981–2.Kuwada K, Kagawa S, Yoshida R, Sakamoto S, Ito A, Watanabe M, Ieda T, Kuroda S, Kikuchi S, Tazawa H, Fujiwara T. The epithelial-to-mesenchymal transition induced by tumor-associated macrophages confers chemoresistance in peritoneally disseminated pancreatic cancer. J Exp Clin Cancer Res. 2018; 37 (1): 307. DOI:10.1186/s13046–018–0981–2.Sanmamed MF, Perez-Gracia JL, Schalper KA, Fusco JP, Gonzalez A, Rodriguez-Ruiz ME, Oñate C, Perez G, Alfaro C, Martín-Algarra S, Andueza MP, Gurpide A, Morgado M, Wang J, Bacchiocchi A, Halaban R, Kluger H, Chen L, Sznol M, Melero I. Changes in serum interleukin‑8 (IL‑8) levels reflect and predict response to anti-PD‑1 treatment in melanoma and non-small-cell lung cancer patients. Ann Oncol. 2017; 28 (8): 1988–1995. DOI:10.1093/annonc/mdx190.Sanmamed MF, Perez-Gracia JL, Schalper KA, Fusco JP, Gonzalez A, Rodriguez-Ruiz ME, Oñate C, Perez G, Alfaro C, Martín-Algarra S, Andueza MP, Gurpide A, Morgado M, Wang J, Bacchiocchi A, Halaban R, Kluger H, Chen L, Sznol M, Melero I. Changes in serum interleukin‑8 (IL‑8) levels reflect and predict response to anti-PD‑1 treatment in melanoma and non-small-cell lung cancer patients. Ann Oncol. 2017; 28 (8): 1988–1995. DOI:10.1093/annonc/mdx190.Butterfield, L.H., Disis, M.L., Fox, B.A. et al. SITC 2018 workshop report: Immuno-Oncology Biomarkers: State of the Art. J. Immunotherapy Cancer. 2018; 6: 138. https://doi.org/10.1186/s40425–018–0453–4Butterfield, L.H., Disis, M.L., Fox, B.A. et al. SITC 2018 workshop report: Immuno-Oncology Biomarkers: State of the Art. J. Immunotherapy Cancer. 2018; 6: 138. https://doi.org/10.1186/s40425–018–0453–4Adam T, Becker TM, Chua W, Bray V, Roberts TL. The Multiple Potential Biomarkers for Predicting Immunotherapy Response-Finding the Needle in the Haystack. Cancers (Basel). 2021; 13 (2): 277. DOI:10.3390/cancers13020277.Adam T, Becker TM, Chua W, Bray V, Roberts TL. The Multiple Potential Biomarkers for Predicting Immunotherapy Response-Finding the Needle in the Haystack. Cancers (Basel). 2021; 13 (2): 277. DOI:10.3390/cancers13020277.Gulley JL, Berzofsky JA, Butler MO, Cesano A, Fox BA, Gnjatic S, Janetzki S, Kalavar S, Karanikas V, Khleif SN, Kirsch I, Lee PP, Maccalli C, Maecker H, Schlom J, Seliger B, Siebert J, Stroncek DF, Thurin M, Yuan J, Butterfield LH. Immunotherapy biomarkers 2016: overcoming the barriers. J Immunother Cancer. 2017; 5 (1): 29. DOI:10.1186/s40425–017–0225–6.Gulley JL, Berzofsky JA, Butler MO, Cesano A, Fox BA, Gnjatic S, Janetzki S, Kalavar S, Karanikas V, Khleif SN, Kirsch I, Lee PP, Maccalli C, Maecker H, Schlom J, Seliger B, Siebert J, Stroncek DF, Thurin M, Yuan J, Butterfield LH. Immunotherapy biomarkers 2016: overcoming the barriers. J Immunother Cancer. 2017; 5 (1): 29. DOI:10.1186/s40425–017–0225–6.Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013; 4: 2612. DOI:10.1038/ncomms3612.Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013; 4: 2612. DOI:10.1038/ncomms3612.Li F, Teng H, Liu M, Liu B, Zhang D, Xu Z, Wang Y and Zhou H. Prognostic Value of Immune-Related Genes in the Tumor Microenvironment of Bladder Cancer. Front. Oncol. 2020; 10: 1302. DOI:10.3389/fonc.2020.01302.Li F, Teng H, Liu M, Liu B, Zhang D, Xu Z, Wang Y and Zhou H. Prognostic Value of Immune-Related Genes in the Tumor Microenvironment of Bladder Cancer. Front. Oncol. 2020; 10: 1302. DOI:10.3389/fonc.2020.01302.Van Kessel KE, de Haan LM, Fransen van de Putte EE, van Rhijn BW, de Wit R, van der Heijden MS, Zwarthoff EC, Boormans JL. Elevated Derived Neutrophil-to-Lymphocyte Ratio Corresponds with Poor Outcome in Patients Undergoing Pre-Operative Chemotherapy in Muscle-Invasive Bladder Cancer. Bladder Cancer. 2016; 2 (3): 351–360. DOI:10.3233/BLC‑160055.Van Kessel KE, de Haan LM, Fransen van de Putte EE, van Rhijn BW, de Wit R, van der Heijden MS, Zwarthoff EC, Boormans JL. Elevated Derived Neutrophil-to-Lymphocyte Ratio Corresponds with Poor Outcome in Patients Undergoing Pre-Operative Chemotherapy in Muscle-Invasive Bladder Cancer. Bladder Cancer. 2016; 2 (3): 351–360. DOI:10.3233/BLC‑160055.Понукалин А. Н., Захарова Н. Б., Чехонацкая М. Л. и др. Система VIRADS и уровни биомаркеров опухолевого микроокружения у больных раком мочевого пузыря при выборе тактики лечения. Онкоурология. 2020; 16(3): 117–25. https://doi.org/10.17650/17269776–2020–16–3–117–125A. N. Ponukalin, N. B. Zakharova, M. L. Chekhonatskaya, et al. VI-RADS system and levels of tumor microenvironment biomarkers in patients with muscle-invasive bladder cancer when choosing treatment tactics. Cancer Urology. 2020; 16 (3): 117–125. (In Russ.) https://doi.org/10.17650/1726–9776–2020–16–3–117–125Wang Z, Liu Y, Zhang Y, Shang Y, Gao Q. MDSC-decreasing chemotherapy increases the efficacy of cytokine-induced killer cell immunotherapy in metastatic renal cell carcinoma and pancreatic cancer. Oncotarget. 2016; 7 (4): 4760–9. DOI:10.18632/oncotarget.6734.Wang Z, Liu Y, Zhang Y, Shang Y, Gao Q. MDSC-decreasing chemotherapy increases the efficacy of cytokine-induced killer cell immunotherapy in metastatic renal cell carcinoma and pancreatic cancer. Oncotarget. 2016; 7 (4): 4760–9. DOI:10.18632/oncotarget.6734.Hah Y.-S.; Koo K.-C. Immunology and Immunotherapeutic Approaches for Advanced Renal Cell Carcinoma: A Comprehensive Review. Int. J. Mol. Sci. 2021, 22, 4452. https://doi.org/10.3390/ijms22094452Hah Y.-S.; Koo K.-C. Immunology and Immunotherapeutic Approaches for Advanced Renal Cell Carcinoma: A Comprehensive Review. Int. J. Mol. Sci. 2021, 22, 4452. https://doi.org/10.3390/ijms22094452Hah Y.-S.; Koo K.-C. Immunology and Immunotherapeutic Approaches for Advanced Renal Cell Carcinoma: A Comprehensive Review. Int. J. Mol. Sci. 2021, 22, 4452. https://doi.org/10.3390/ijms22094452Hah Y.-S.; Koo K.-C. Immunology and Immunotherapeutic Approaches for Advanced Renal Cell Carcinoma: A Comprehensive Review. Int. J. Mol. Sci. 2021, 22, 4452. https://doi.org/10.3390/ijms22094452Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, Eigl BJ, Ruether JD, Cheng T, North S, Venner P, Knox JJ, Chi KN, Kollmannsberger C, McDermott DF, Oh WK, Atkins MB, Bukowski RM, Rini BI, Choueiri TK. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009; 27 (34): 5794–9. DOI:10.1200/JCO.2008.21.4809.Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, Eigl BJ, Ruether JD, Cheng T, North S, Venner P, Knox JJ, Chi KN, Kollmannsberger C, McDermott DF, Oh WK, Atkins MB, Bukowski RM, Rini BI, Choueiri TK. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009; 27 (34): 5794–9. DOI:10.1200/JCO.2008.21.4809.Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, Rha SY, Agarwal N, Kollmannsberger C, Rini BI, Choueiri TK. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013; 14 (2): 141–8. DOI:10.1016/S1470–2045(12)70559–4Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, Rha SY, Agarwal N, Kollmannsberger C, Rini BI, Choueiri TK. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013; 14 (2): 141–8. DOI:10.1016/S1470–2045(12)70559–4Santoni M, Massari F, Di Nunno V, Conti A, Cimadamore A, Scarpelli M, et al. Immunotherapy in renal cell carcinoma: latest evidence and clinical implications. Drugs Context (2018) 7: 212528. DOI:10.7573/dic.212528.Santoni M, Massari F, Di Nunno V, Conti A, Cimadamore A, Scarpelli M, et al. Immunotherapy in renal cell carcinoma: latest evidence and clinical implications. Drugs Context (2018) 7: 212528. DOI:10.7573/dic.212528.Montironi R, Lopez-Beltran A, Cheng L. Editorial: emerging biomarkers in genitourinary tumors. Curr Drug Metab. (2017) 18: 690–91. DOI:10.2174/138920021808171016103101.Montironi R, Lopez-Beltran A, Cheng L. Editorial: emerging biomarkers in genitourinary tumors. Curr Drug Metab. (2017) 18: 690–91. DOI:10.2174/138920021808171016103101.Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature (2010) 463: 360–3. DOI:10.1038/nature08672.Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature (2010) 463: 360–3. DOI:10.1038/nature08672.Montironi R, Santoni M, Cheng L, Lopez-Beltran A, Massari F, Matrana MR, et al. An overview of emerging immunotargets of genitourinary tumors. Curr Drug Targets (2016) 17: 750–6. DOI:10.2174/1389450117666151209144649.Montironi R, Santoni M, Cheng L, Lopez-Beltran A, Massari F, Matrana MR, et al. An overview of emerging immunotargets of genitourinary tumors. Curr Drug Targets (2016) 17: 750–6. DOI:10.2174/1389450117666151209144649.Slovin SF. The need for immune biomarkers for treatment prognosis and response in genitourinary malignancies. Biomark Med. (2017) 11: 1149–59. DOI:10.2217/bmm‑2017–0138.Slovin SF. The need for immune biomarkers for treatment prognosis and response in genitourinary malignancies. Biomark Med. (2017) 11: 1149–59. DOI:10.2217/bmm‑2017–0138.Ciccarese C, Santoni M, Massari F, Cheng L, Lopez-Beltran A, Scarpelli M, et al. Present and future of personalized medicine in adult genitourinary tumors. Fut Oncol. (2015) 11: 1381–8. DOI:10.2217/fon.15.30.Ciccarese C, Santoni M, Massari F, Cheng L, Lopez-Beltran A, Scarpelli M, et al. Present and future of personalized medicine in adult genitourinary tumors. Fut Oncol. (2015) 11: 1381–8. DOI:10.2217/fon.15.30.Lopez-Beltran A, Henriques V, Cimadamore A, Santoni M, Cheng L, Gevaert T, Blanca A, Massari F, Scarpelli M and Montironi R. The Identification of Immunological Biomarkers in Kidney Cancers. Front. Oncol. 2018; 8: 456. DOI:10.3389/fonc.2018.00456.Lopez-Beltran A, Henriques V, Cimadamore A, Santoni M, Cheng L, Gevaert T, Blanca A, Massari F, Scarpelli M and Montironi R. The Identification of Immunological Biomarkers in Kidney Cancers. Front. Oncol. 2018; 8: 456. DOI:10.3389/fonc.2018.00456.Bahmad HF, Jalloul M, Azar J, Moubarak MM, Samad TA, Mukherji D, AlSayegh M and Abou-Kheir W Tumor Microenvironment in Prostate Cancer: Toward Identification of Novel Molecular Biomarkers for Diagnosis, Prognosis, and Therapy Development. Front. Genet. 2021; 12: 652747. DOI:10.3389/fgene.2021.652747.Bahmad HF, Jalloul M, Azar J, Moubarak MM, Samad TA, Mukherji D, AlSayegh M and Abou-Kheir W Tumor Microenvironment in Prostate Cancer: Toward Identification of Novel Molecular Biomarkers for Diagnosis, Prognosis, and Therapy Development. Front. Genet. 2021; 12: 652747. DOI:10.3389/fgene.2021.652747.Massari F, Modena A, Ciccarese C, Pilotto S, Maines F, Bracarda S, Sperduti I, Giannarelli D, Carlini P, Santini D, Tortora G, Porta C, Bria E. Addressing the expected survival benefit for clinical trial design in metastatic castration-resistant prostate cancer: Sensitivity analysis of randomized trials. Crit Rev Oncol Hematol. 2016; 98: 254–63. DOI:10.1016/j.critrevonc.2015.11.009.Massari F, Modena A, Ciccarese C, Pilotto S, Maines F, Bracarda S, Sperduti I, Giannarelli D, Carlini P, Santini D, Tortora G, Porta C, Bria E. Addressing the expected survival benefit for clinical trial design in metastatic castration-resistant prostate cancer: Sensitivity analysis of randomized trials. Crit Rev Oncol Hematol. 2016; 98: 254–63. DOI:10.1016/j.critrevonc.2015.11.009.Drake CG, Sharma P, Gerritsen W. Metastatic castration-resistant prostate cancer: new therapies, novel combination strategies and implications for immunotherapy. Oncogene. 2014; 33 (43): 5053–64. DOI:10.1038/onc.2013.497.Drake CG, Sharma P, Gerritsen W. Metastatic castration-resistant prostate cancer: new therapies, novel combination strategies and implications for immunotherapy. Oncogene. 2014; 33 (43): 5053–64. DOI:10.1038/onc.2013.497.Constantin N Baxevanis, Michael Papamichail & Sonia A Perez Immunologic Biomarkers in prostate cancer, Human Vaccines & Immunotherapeutics,2014; 10 (5): 1244–1247, DOI:10.4161/hv.28032.Constantin N Baxevanis, Michael Papamichail & Sonia A Perez Immunologic Biomarkers in prostate cancer, Human Vaccines & Immunotherapeutics,2014; 10 (5): 1244–1247, DOI:10.4161/hv.28032.De Velasco MA, Uemura H. Prostate cancer immunotherapy: where are we and where are we going? Curr Opin Urol. 2018; 28 (1): 15–24. DOI:10.1097/MOU.0000000000000462.De Velasco MA, Uemura H. Prostate cancer immunotherapy: where are we and where are we going? Curr Opin Urol. 2018; 28 (1): 15–24. DOI:10.1097/MOU.0000000000000462.Adam T, Becker TM, Chua W, Bray V, Roberts TL.The Multiple Potential Biomarkers for Predicting Immunotherapy Response-Finding the Needle in the Haystack. Cancers (Basel). 2021; 13 (2): 277. DOI:10.3390/cancers13020277.Adam T, Becker TM, Chua W, Bray V, Roberts TL.The Multiple Potential Biomarkers for Predicting Immunotherapy Response-Finding the Needle in the Haystack. Cancers (Basel). 2021; 13 (2): 277. DOI:10.3390/cancers13020277.

The authors declare that there are no conflicts of interest present.