Клеточное микроокружение как объект таргетной терапии злокачественных новообразований

Динамические взаимоотношения между опухолевыми клетками и их микроокружением имеют решающее значение в развитии и прогрессировании злокачественного процесса. С учетом мультифункционального потенциала гетерогенных популяций, окружающих опухоль, нацеливание на компоненты микроокружения уже давно рассматривается как перспективная стратегия в современной терапии новообразований. В настоящем  обзоре проанализированы роль компонентов клеточного микроокружения в канцерогенезе, а также пути и механизмы воздействия на основные популяции клеток, представляющие наибольший интерес в контексте разработки новых подходов к лечению злокачественных опухолей.

1. Koontongkaew S. The tumor microenvironment contribution to development, growth, invasion and metastasis of head and neck squamous cell carcinomas. J Cancer 2013;4(1):66–83. DOI: 10.7150/jca.5112

2. Зибиров Р.Ф., Мозеров С.А. Характеристика клеточного микроокружения опухоли. Онкология. Журнал им. П.А. Герцена 2018;7(2):67–72. DOI: 10.17116/onkolog20187267-72

3. Атаи А., Соловьева В.В., Ризванов А.А., Араб С.Ш. Микроокружение опухоли: ключевой фактор развития рака, инвазии и лекарственной устойчивости. Ученые записки Казанского университета. Серия «Естественные науки» 2020;162:507–28. DOI: 10.26907/2542-064X.2020.4.507-528

4. Крахмаль Н.В., Завьялова М.В., Денисов Е.В. и др. Инвазия опухолевых эпителиальных клеток: механизмы и проявления. Acta Naturae 2015;7(2):18–31.

5. Dudley A.C. Tumor endothelial cells. Cold Spring Harb Perspect Med 2012;2(3):a006536. DOI: 10.1101/cshperspect.a006536

6. Baghban R., Roshangar L., Jahanban-Esfahlan R. et al. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun Signal 2020;18(1):59. DOI: 10.1186/s12964-020-0530-4

7. Gille H., Kowalski J., Li B. et al. Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2): a reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem 2001;276:3222–30. DOI: 10.1074/jbc.M002016200

8. Daei Farshchi Adli A., Jahanban-Esfahlan R., Seidi K. et al. An overview on Vadimezan (DMXAA): The vascular disrupting agent. Chem Biol Drug Des 2018;91(5):996–1006. DOI: 10.1111/cbdd.13166

9. Zhang Y., Xiong X., Huai Y. et al. Gold nanoparticles disrupt tumor microenvironment – endothelial cell cross talk to inhibit angiogenic phenotypes in vitro. Bioconjug Chem 2019;30(6):1724–33. DOI: 10.1021/acs.bioconjchem.9b00262

10. Nomura T., Yamakawa M., Shimaoka T. et al. Development of dendritic cell-based immunotherapy targeting tumor blood vessels in a mouse model of lung metastasis. Biol Pharm Bull 2019;42(4):645–8. DOI: 10.1248/bpb.b18-00737

11. Liu T., Zhou L., Li D. et al. Cancer-associated fibroblasts build and secure the tumor microenvironment. Front Cell Dev Biol 2019;7:60. DOI: 10.3389/fcell.2019.00060

12. Puré E., Hingorani S.R. Mesenchymal cell plasticity and perfidy in epithelial malignancy. Trends Cancer 2018;4(4):273–7. DOI: 10.1016/j.trecan.2018.02.007

13. Shiga K., Hara M., Nagasaki T. et al. Cancer-associated fibroblasts: their characteristics and their roles in tumor growth. Cancers 2015;7(4):2443–58. DOI: 10.3390/cancers7040902

14. Ермаков М.С., Нуштаева А.А., Рихтер В.А., Коваль О.А. Опухоль-ассоциированные фибробласты и их роль в опухолевой прогреcсии. Вавиловский журнал генетики и селекции 2022;26(1):14–21. DOI: 10.18699/VJGB-22-03

15. Hosein A.N., Wu M., Arcand S.L. et al. Breast carcinoma-associated fibroblasts rarely contain p53 mutations or chromosomal aberrations. Cancer Res 2010;70(14):5770–7. DOI: 10.1158/0008-5472.CAN-10-0673

16. Олейникова Н.А., Данилова Н.В., Михайлов И.А. и др. Опухоль-ассоциированные фибробласты и их значение в прогрессии злокачественных новообразований. Архив патологии 2020;82(1):68–77. DOI: 10.17116/patol20208201168

17. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer 2016;16(9):582–98. DOI: 10.1038/nrc.2016.73

18. Monteran L., Erez N. The dark side of fibroblasts: cancer-associated fibroblasts as mediators of immunosuppression in the tumor microenvironment. Front Immunol 2019;10:1835. DOI: 10.3389/fimmu.2019.01835

19. Jones J.O., Moody W.M., Shields J.D. Microenvironmental modulation of the developing tumor: an immune-stromal dialogue. Mol Oncol 2021;15(10):2600–33. DOI: 10.1002/1878-0261.12773

20. Pavlides S., Whitaker-Menezes D., Castello-Cros R. et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 2009;8(23):3984–4001. DOI: 10.4161/cc.8.23.10238

21. Jiang G.M,. Xu W., Du J. et al. The application of the fibroblast activation protein alpha-targeted immunotherapy strategy. Oncotarget 2016;7(22):33472–82. DOI: 10.18632/oncotarget.8098

22. Yoshida T., Ishii G., Goto K. et al. Podoplanin-positive cancer-associated fibroblasts in the tumor microenvironment induce primary resistance to EGFR-TKIs in lung adenocarcinoma with EGFR mutation. Clinl Cancer Res 2015;21(3):642–51. DOI: 10.1158/1078-0432.CCR-14-0846

23. Noy R., Pollard J.W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 2014;41(1):49–61. DOI: 10.1016/j.immuni.2014.06.010

24. Laviron M., Boissonnas A. Ontogeny of tumor-associated macrophages. Front Immunol 2019;10:1799. DOI: 10.3389/fimmu.2019.01799

25. Mantovani A., Sica A., Sozzani S. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 2004;25(12):677–86. DOI: 10.1016/j.it.2004.09.015

26. Nesbit M., Schaider H., Miller T.H., Herlyn M. Low-level monocyte chemoattractant protein-1 stimulation of monocytes leads to tumor formation in nontumorigenic melanoma cells. J Immunol 2001;166(11):6483–90. DOI: 10.4049/jimmunol.166.11.6483

27. Porta C., Subhra Kumar B., Larghi P. et al. Tumor promotion by tumor-associated macrophages. Adv Exp Med Biol 2007;604: 47–86. DOI: 10.1007/978-0-387-69116-9_5

28. Valkovic T., Dobrila F., Melato M. et al. Correlation between vascular endothelial growth factor, angiogenesis and tumor-associated macrophages in invasive ductal breast carcinoma. Virchows Arch 2002;440(6):583–8. DOI: 10.1007/s004280100458

29. Chen Y., Tan W., Wang C. Tumor-associated macrophage-derived cytokines enhance cancer stem-like characteristics through epithelial-mesenchymal transition. Onco Targets Ther 2018;11:3817–26. DOI: 10.2147/OTT.S168317

30. Mantovani A., Marchesi F., Malesci A. et al. Tumor-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 2017;14(7):399–416. DOI: 10.1038/nrclinonc.2016.217

31. Van Rooijen N., Sanders A. Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Methods 1994;174(1–2):83–93. DOI: 10.1016/0022-1759(94)90012-4

32. Banciu M., Metselaar J.M., Schiffelers R.M., Storm G. Antitumor activity of liposomal prednisolone phosphate depends on the presence of functional tumor-associated macrophages in tumor tissue. Neoplasia 2008;10(2):108–17. DOI: 10.1593/neo.07913

33. Sato K., Fujita S. Dendritic cells: nature and classification. Allergol Int 2007;56(3):183–91. DOI: 10.2332/allergolint.R-06-139

34. Олейник Е.К., Шибаев М.И., Игнатьев К.С. и др. Микроокружение опухоли: формирование иммунного профиля. Медицинская иммунология 2020;22(2):207–20. DOI: 10.15789/1563-0625-TMT-1909

35. Shurin M.R., Yurkovetsky Z.R., Tourkova I.L. Inhibition of CD40 expression and CD40-mediated dendritic cell function by tumor-derived IL-10. Int J Cancer 2002;101(1):61–8. DOI: 10.1002/ijc.10576

36. Manavalan J.S., Rossi P.C., Vlad G. et al. High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells. Transpl Immunol 2003;11(3–4):245–58. DOI: 10.1016/s0966-3274(03)00058-3

37. Liu Q., Zhang C., Sun A. et al. Tumor-educated CD11 bhighIalow regulatory dendritic cells suppress T cell response through arginase I. J Immunol 2009;182(10):6207–16. DOI: 10.4049/jimmunol.0803926

38. Anandasabapathy N., Victora G.D., Meredith M. et al. Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain. J Exp Med 2011;208(8):1695–705. DOI: 10.1084/jem.20102657

39. Salmon H., Idoyaga J., Rahman A. et al. Expansion and activation of CD103(+) dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 2016;44(4):924–38. DOI: 10.1016/j.immuni.2016.03.012

40. Anandasabapathy N., Breton G., Hurley A. et al. Efficacy and safety of CDX-301, recombinant human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human volunteers. Bone Marrow Transplant 2015;50(7):924–30. DOI: 10.1038/bmt.2015.74

41. Agrawal V., Benjamin K.T., Ko E.C. Radiotherapy and immunotherapy combinations for lung cancer. Curr Oncol Rep 2020;23(1):4. DOI: 10.1007/s11912-020-00993-w

42. Anguille S., Smits E.L., Lion E. et al. Clinical use of dendritic cells for cancer therapy. Lancet Oncol 2014;15(7):e257–67. DOI: 10.1016/s1470-2045(13)70585-0

43. Jiang Y., Li Y., Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis 2015;6(6):e1792. DOI: 10.1038/cddis.2015.162

44. Chang C.H., Curtis J.D., Maggi L.B. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013;153(6):1239–51. DOI: 10.1016/j.cell.2013.05.016

45. Fife B.T., Bluestone J.A. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 2008;224:166–82. DOI: 10.1111/j.1600-065X.2008.00662.x

46. Leach D.R., Krummel M.F., Allison J.P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271(5256):1734–6. DOI: 10.1126/science.271.5256.1734

47. Kwon E.D., Hurwitz A.A., Foster B.A. et al. Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer. Proc Natl Acad Sci USA 1997;94(15):8099–103. DOI: 10.1073/pnas.94.15.8099

48. Hurwitz A.A., Yu T.F., Leach D.R., Allison J.P. CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma. Proc Natl Acad Sci USA 1998;95(17):10067–71. DOI: 10.1073/pnas.95.17.10067

49. 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: 10.1056/NEJMoa1003466

50. Weber J.S., D’Angelo S.P., Minor D. et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015;16(4):375–84. DOI: 10.1016/S1470-2045(15)70076-8

51. 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: 10.1056/NEJMoa1503093

52. 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: 10.1056/NEJMoa1412082

53. Gong J., Chehrazi-Raffle A., Reddi S., Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer 2018;6(1):8. DOI: 10.1186/s40425-018-0316-z

54. Mann J.E. Atezolizumab (tecentriq®). Oncology Times 2017;39(4):31. DOI: 10.1097/01.cot.0000513325.52233.f1

55. Златник Е.Ю., Ситковская А.О., Непомнящая Е.М. и др. Достижения и перспективы клеточных технологий на основе активированных лимфоцитов в лечении злокачественных опухолей. Казанский медицинский журнал 2018;99(5):792–801. DOI: 10.17816/KMJ2018–792

56. Rosenberg S.A., Mulé J.J., Spiess P.J. et al. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med 1985;161(5):1169–88. DOI: 10.1084/jem.161.5.1169

57. Jackson H.J., Rafiq S., Brentjens R.J. Driving CAR T-cells forward. Nat Rev Clin Oncol 2016;13(6):370–83. DOI: 10.1038/nrclinonc.2016.36

58. Устюгова Е.А., Савкина М.В., Горяев А.А. и др. Применение биомедицинских клеточных продуктов для лечения онкологических заболеваний. БИО препараты. Профилактика, диагностика, лечение 2019;19(4):206–14. DOI: 10.30895/2221-996X-2019-19-4-206-214

59. Chang Z.L., Lorenzini M.H., Chen X. et al. Rewiring T-cell responses to soluble factors with chimeric antigen receptors. Nat Chem Biol 2018;14(3):317–24. DOI: 10.1038/nchembio.2565

60. Hartmann J., Schüßler-Lenz M., Bondanza A., Buchholz C.J. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med 2017;9(9):1183–97. DOI: 10.15252/emmm.201607485