Современные аспекты иммунотерапии ингибиторами контрольных точек при меланоме

Хотя меланома является одной из наиболее иммуногенных опухолей, она обладает способностью уклоняться от противоопухолевого иммунного ответа, используя механизмы толерантности. В этой связи наиболее широко изученными контрольными точками являются белок‑4, ассоциированный с цитотоксическими Т-лимфоцитами (CTLA‑4), и белок‑1 запрограммированной гибели клеток (PD‑1), ставшие мишенями в терапии этого заболевания. Ингибиторы иммунных контрольных точек (ИКТ) стали широко применяться для лечения меланомы в последнее десятилетие. Пациенты, ответившие на лечение ИКТ, могут иметь длительную ремиссию или контроль заболевания. Однако не все больные отвечают на эту терапию или со временем прогрессируют, что свидетельствует о развитии механизмов резистентности. Среди них – особенности опухоли, дисфункция эффекторных клеток и образование иммуносупрессивного опухолевого микроокружения (ТМЕ). Обсуждаются достижения в лечении меланомы ИКТ, причины неэффективности и перспективные подходы для преодоления резистентности, такие как комбинации различных ИКТ друг с другом, стратегии нейтрализации иммуносупрессивного ТМЕ и сочетание ИКТ с другими противоопухолевыми методами лечения – лучевой, онколитической вирусной или таргетной терапией. Также обсуждаются новые терапевтические подходы, нацеленные на другие молекулы иммунных контрольных точек.

1. Dunn G.P., Bruce A. T., Ikeda H., Old L. J., Schreiber R.D. Cancer immunoediting: From immunosurveillance to tumor escape. Nat. Immunol. 2002; 3: 991–998. DOI: 10.1038/ni1102–991.

2. Ribatti D. The concept of immune surveillance against tumors. The first theories. Oncotarget. 2017; 8: 7175–7180. DOI: 10.18632/oncotarget.12739.

3. Chalmers Z.R., Connelly C. F., Fabrizio D., Gay L., Ali S.M., Ennis R., Schrock A., Campbell B., Shlien A., Chmielecki J., et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017; 9: 34. DOI: 10.1186/s13073–017–0424–2.

4. Pitcovski J., Shahar E., Aizenshtein E., Gorodetsky R. Melanoma antigens and related immunological markers. Crit. Rev. Oncol. Hematol. 2017; 115: 36–49. DOI: 10.1016/j.critrevonc.2017.05.001.

5. Schreiber R.D., Old L. J., Smyth M. J. Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science. 2011; 331: 1565–1570. DOI: 10.1126/science.1203486.

6. Ott P. A., Hu Z., Keskin D. B., Shukla S. A., Sun J., Bozym D. J., Zhang W., Luoma A., Giobbie-Hurder A., Peter L., et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. 2017; 547: 217–221. DOI: 10.1038/nature22991.

7. Rohaan M.W., Van Den Berg J.H., Kvistborg P., Haanen J.B.A.G. Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: A viable treatment option. J. Immunother. Cancer. 2018; 6: 102. DOI: 10.1186/s40425–018–0391–1.

8. Ottaviano M., De Placido S., Ascierto P. A. Recent success and limitations of immune checkpoint inhibitors for cancer: A lesson from melanoma. Virchows Arch. 2019; 474: 421–432. DOI: 10.1007/s00428–019–02538–4.

9. Luke J. J., Flaherty K. T., Ribas A., Long G.V. Targeted agents and immunotherapies: Optimizing outcomes in melanoma. Nat. Rev. Clin. Oncol. 2017; 14: 463–482. DOI: 10.1038/nrclinonc.2017.43.

10. Sansom D.M. CD28, CTLA-4 and their ligands: Who does what and to whom? Immunology. 2000; 101: 169–177. DOI: 10.1046/j.1365–2567.2000.00121.x.

11. Alsaab H.O., Sau S., Alzhrani R., Tatiparti K., Bhise K., Kashaw S.K., Iyer A.K. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: Mechanism, combinations, and clinical outcome. Front. Pharmacol. 2017; 8: 561. DOI: 10.3389/fphar.2017.00561.

12. Gellrich F. F., Schmitz M., Beissert S., Meier F. Meier Anti-PD-1 and Novel Combinations in the Treatment of Melanoma – ​An Update. J. Clin. Med. 2020; 9: 223. DOI: 10.3390/jcm9010223.

13. Gide T.N., Quek C., Menzies A.M., Tasker A.T., Shang P., Holst J., Madore J., Lim S.Y., Velickovic R., Wongchenko M., et al. Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy. Cancer Cell. 2019; 35: 238–255. DOI: 10.1016/j.ccell.2019.01.003.

14. Zhao Y., Lee C.K., Lin C.H., Gassen R. B., Xu X., Huang Z., Xiao C., Bonorino C., Lu L. F., Bui J.D., et al. PD-L1: CD80 Cis-Heterodimer Triggers the Co-stimulatory Receptor CD 28 While Repressing the Inhibitory PD-1 and CTLA-4 Pathways. Immunity. 2019; 51: 1059–1073. DOI: 10.1016/j.immuni.2019.11.003.

15. Wessely A., Steeb T., Erdmann M., Heinzerling L., Vera J., Schlaak M., Berking C., Heppt M.V. Wessely; Steeb; Erdmann; Heinzerling; Vera; Schlaak; Berking; Heppt The Role of Immune Checkpoint Blockade in Uveal Melanoma. Int. J. Mol. Sci. 2020; 21: 879. DOI: 10.3390/ijms21030879.

16. Michielin O., van Akkooi A., Ascierto P., Dummer R., Keilholz U. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2019; 30: 1884–1901. DOI: 10.1093/annonc/mdz411.

17. Weber J., Mandala M., Del Vecchio M., Gogas H. J., Arance A.M., Cowey C. L., Dalle S., Schenker M., Chiarion-Sileni V., Marquez-Rodas I., et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N. Engl. J. Med. 2017; 377: 1824–1835. DOI: 10.1056/NEJMoa1709030.

18. Amaria R.N., Reddy S.M., Tawbi H.A., Davies M.A., Ross M.I., Glitza I.C., Cormier J.N., Lewis C., Hwu W. J., Hanna E., et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 2018; 24: 1649–1654. DOI: 10.1038/s41591–018–0197–1.

19. Seymour L., Bogaerts J., Perrone A., Ford R., Schwartz L.H., Mandrekar S., Lin N.U., Litière S., Dancey J., Chen A., et al. iRECIST: Guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017; 18: e143–e152. DOI: 10.1016/S1470–2045(17)30074–8.

20. Hodi F. S., Chiarion-Sileni V., Gonzalez R., Grob J. J., Rutkowski P., Cowey C. L., Lao C.D., Schadendorf D., Wagstaff J., Dummer R., et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018; 19: 1480–1492. DOI: 10.1016/S1470–2045(18)30700–9.

21. Larkin J., Chiarion-Sileni V., Gonzalez R., Grob J. J., Rutkowski P., Lao C. D., Cowey C.L., Schadendorf D., Wagstaff J., Dummer R., et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 2019; 381: 1535–1546. DOI: 10.1056/NEJMoa1910836.

22. Long G.V., Atkinson V., Cebon J. S., Jameson M.B., Fitzharris B.M., McNeil C.M., Hill A.G., Ribas A., Atkins M.B., Thompson J.A., et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): An open-label, phase 1b trial. Lancet. Oncol. 2017; 18: 1202–1210. DOI: 10.1016/S1470–2045(17)30428-X.

23. Somasundaram R., Herlyn M., Wagner S.N. The role of tumor microenvironment in melanoma therapy resistance. Melanoma Manag. 2016; 3: 23–32. DOI: 10.2217/mmt.15.37.

24. Seliger B. Basis of PD1/PD-L1 Therapies. J. Clin. Med. 2019; 8: 2168. DOI: 10.3390/jcm8122168.

25. Rodig S. J., Gusenleitner D., Jackson D. G., Gjini E., Giobbie-Hurder A., Jin C., Chang H., Lovitch S.B., Horak C., Weber J.S., et al. MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Sci. Transl. Med. 2018; 10: eaar3342. DOI: 10.1126/scitranslmed.aar3342.

26. Verma V., Shrimali R.K., Ahmad S., Dai W., Wang H., Lu S., Nandre R., Gaur P., Lopez J., Sade-Feldman M., et al. PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance. Nat. Immunol. 2019; 20: 1231–1243. DOI: 10.1038/s41590–019–0441-y.

27. Poggio M., Hu T., Pai C.C., Chu B., Belair C.D., Chang A., Montabana E., Lang U.E., Fu Q., Fong L., et al. Suppression of Exosomal PD-L1 Induces Systemic Anti-Tumor Immunity and Memory. Cell. 2019; 177: 414–427. DOI: 10.1016/j.cell.2019.02.016.

28. Veglia F., Perego M., Gabrilovich D. Myeloid-derived suppressor cells coming of age review-article. Nat. Immunol. 2018; 19: 108–119. DOI: 10.1038/s41590–017–0022-x.

29. Bronte V., Brandau S., Chen S.H., Colombo M.P., Frey A.B., Greten T.F., Mandruzzato S., Murray P.J., Ochoa A., Ostrand-Rosenberg S., et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 2016; 7: 12150. DOI: 10.1038/ncomms12150.

30. Noman M. Z., Desantis G., Janji B., Hasmim M., Karray S., Dessen P., Bronte V., Chouaib S. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced: MDSC-mediated T cell activation. J. Exp. Med. 2014; 211: 781–790. DOI: 10.1084/jem.20131916.

31. Groth C., Hu X., Weber R., Fleming V., Altevogt P., Utikal J., Umansky V. Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression. Br. J. Cancer. 2019; 120: 16–25. DOI: 10.1038/s41416–018–0333–1.

32. Gabrilovich D. I., Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 2009; 9: 162–174. DOI: 10.1038/nri2506.

33. Jiang H., Gebhardt C., Umansky L., Beckhove P., Schulze T. J., Utikal J., Umansky V. Elevated chronic inflammatory factors and myeloid-derived suppressor cells indicate poor prognosis in advanced melanoma patients. Int. J. Cancer. 2015; 136: 2352–2360. DOI: 10.1002/ijc.29297.

34. Weber J., Gibney G., Kudchadkar R., Yu B., Cheng P., Martinez A. J., Kroeger J., Richards A., McCormick L., Moberg V., et al. Phase I/II study of metastatic melanoma patients treated with nivolumab who had progressed after ipilimumab. Cancer Immunol. Res. 2016; 4: 345–353. DOI: 10.1158/2326–6066.CIR-15–0193.

35. Fleming V., Hu X., Weber R., Nagibin V., Groth C., Altevogt P., Utikal J., Umansky V. Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression. Front. Immunol. 2018; 9: 398. DOI: 10.3389/fimmu.2018.00398.

36. Iclozan C., Antonia S., Chiappori A., Chen D. T., Gabrilovich D. Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer. Cancer Immunol. Immunother. 2013; 62: 909–918. DOI: 10.1007/s00262–013–1396–8.

37. Ko J. S., Zea A.H., Rini B. I., Ireland J. L., Elson P., Cohen P., Golshayan A., Rayman P.A., Wood L., Garcia J., et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin. Cancer Res. 2009; 15: 2148–2157. DOI: 10.1158/1078–0432.CCR-08–1332.

38. Zhang Y., Bush X., Yan B., Chen J.A. Gemcitabine nanoparticles promote antitumor immunity against melanoma. Biomaterials. 2019; 189: 48–59. DOI: 10.1016/j.biomaterials.2018.10.022.

39. Meyer C., Sevko A., Ramacher M., Bazhin A. V., Falk C. S., Osena W., Borrello I., Kato M., Schadendorf D., Baniyash M., et al. Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model. Proc. Natl. Acad. Sci. USA. 2011; 108: 17111–17116. DOI: 10.1073/pnas.1108121108.

40. Hassel J.C., Jiang H., Bender C., Winkler J., Sevko A., Shevchenko I., Halama N., Dimitrakopoulou-Strauss A., Haefeli W.E., Jäger D., et al. Tadalafil has biologic activity in human melanoma. Results of a pilot trial with Tadalafil in patients with metastatic Melanoma (TaMe) Oncoimmunology. 2017; 6: e1326440. DOI: 10.1080/2162402X.2017.1326440.

41. Sun L., Clavijo P.E., Robbins Y., Patel P., Friedman J., Greene S., Das R., Silvin C., Van Waes C., Horn L.A., et al. Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy. JCI Insight. 2019; 4: 1–12. DOI: 10.1172/jci.insight.126853.

42. Coffelt S.B., Wellenstein M.D., De Visser K. E. Neutrophils in cancer: Neutral no more. Nat. Rev. Cancer. 2016; 16: 431–446. DOI: 10.1038/nrc.2016.52.

43. Moses K., Brandau S. Human neutrophils: Their role in cancer and relation to myeloid-derived suppressor cells. Semin. Immunol. 2016; 28: 187–196. DOI: 10.1016/j.smim.2016.03.018.

44. Zaragoza J., Caille A., Beneton N., Bens G., Christiann F., Maillard H., Machet L. High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment is associated with reduced overall survival in patients with melanoma. Br. J. Dermatol. 2016; 174: 146–151. DOI: 10.1111/bjd.14155.

45. Kalluri R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer. 2016; 16: 582–598. DOI: 10.1038/nrc.2016.73.

46. Paraiso K.H.T., Smalley K. S.M. Fibroblast-mediated drug resistance in cancer. Biochem. Pharmacol. 2013; 85: 1033–1041. DOI: 10.1016/j.bcp.2013.01.018.

47. Wong P.F., Wei W., Gupta S., Smithy J.W., Zelterman D., Kluger H.M., Rimm D.L. Multiplex quantitative analysis of cancer-associated fibroblasts and immunotherapy outcome in metastatic melanoma. J. Immunother. Cancer. 2019; 7: 194. DOI: 10.1186/s40425–019–0675–0.

48. Denton A.E., Roberts E.W., Fearon D. T. Stromal Cells in the Tumor Microenvironment. Adv. Exp. Med. Biol. 2018; 1060: 99–114.

49. Zhao F., Evans K., Xiao C., DeVito N., Theivanthiran B., Holtzhausen A., Siska P. J., Blobe G. C., Hanks B. A. Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma. Cancer Immunol. Res. 2018; 6: 1459–1471. DOI: 10.1158/2326–6066.CIR-18–0086.

50. Wang H., Yang L., Wang D., Zhang Q., Zhang L. Pro-tumor activities of macrophages in the progression of melanoma. Hum. Vaccin. Immunother. 2017; 13: 1556–1562. DOI: 10.1080/21645515.2017.1312043.

51. Salmi S., Siiskonen H., Sironen R., Tyynelä-Korhonen K., Hirschovits-Gerz B., Valkonen M., Auvinen P., Pasonen-Seppänen S. The number and localization of CD68+ and CD163+ macrophages in different stages of cutaneous melanoma. Melanoma Res. 2019; 29: 237–247. DOI: 10.1097/CMR.0000000000000522.

52. Gartrell-Corrado R.D., Chen A.X., Rizk E.M., Marks D.K., Bogardus M.H., Hart T.D., Silverman A.M., Bayan C.-A.Y., Finkel G.G., Barker L.W., et al. Linking transcriptomic and imaging data defines features of a favorable tumor immune microenvironment and identifies a combination biomarker for primary melanoma. Cancer Res. 2020; 80: 1078–1087. DOI: 10.1158/0008–5472.CAN-19–2039.

53. Han N., Baghdadi M., Ishikawa K., Endo H., Kobayashi T., Wada H., Imafuku K., Hata H., Seino K. Enhanced IL-34 expression in Nivolumab-resistant metastatic melanoma. Inflamm. Regen. 2018; 38: 3. DOI: 10.1186/s41232–018–0060–2.

54. Baumgartner J., Wilson C., Palmer B., Richter D., Banerjee A., McCarter M. Melanoma Induces Immunosuppression by Up-Regulating FOXP3+ Regulatory T Cells. J. Surg. Res. 2007; 141: 72–77. DOI: 10.1016/j.jss.2007.03.053.

55. Ward-Hartstonge K.A., Kemp R. A. Regulatory T-cell heterogeneity and the cancer immune response. Clin. Transl. Immunol. 2017; 6: e154. DOI: 10.1038/cti.2017.43.

56. Ha D., Tanaka A., Kibayashi T., Tanemura A., Sugiyama D., Wing J. B., Lim E. L., Teng K.W.W., Adeegbe D., Newell E.W., et al. Differential control of human Treg and effector T cells in tumor immunity by Fc-engineered anti-CTLA-4 antibody. Proc. Natl. Acad. Sci. USA. 2019; 116:609–618. DOI: 10.1073/pnas.1812186116.

57. Sharma A., Subudhi S.K., Blando J., Scutti J., Vence L., Wargo J., Allison J.P., Ribas A., Sharma P. Anti-CTLA-4 immunotherapy does not deplete Foxp3 þ regulatory T cells (Tregs) in human cancers. Clin. Cancer Res. 2019; 25: 1233–1238. DOI: 10.1158/1078–0432.CCR-18–0762.

58. Simpson T. R., Li F., Montalvo-Ortiz W., Sepulveda M. A., Bergerhoff K., Arce F., Roddie C., Henry J.Y., Yagita H., Wolchok J.D., et al. Fc-dependent depletion of tumor-infiltrating regulatory t cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 2013; 210: 1695–1710. DOI: 10.1084/jem.20130579.

59. Bentebibel S. E., Hurwitz M. E., Bernatchez C., Haymaker C., Hudgens C. W., Kluger H.M., Tetzlaff M. T., Tagliaferri M.A., Zalevsky J., Hoch U., et al. A first-in-human study and biomarker analysis of NKTR-214, a novel IL2Rβγ-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov. 2019; 9: 711–721. DOI: 10.1158/2159–8290.CD-18–1495.

60. Robert C., Schachter J., Long G.V., Arance A., Grob J.J., Mortier L., Daud A., Carlino M.S., McNeil C., Lotem M., et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 2015; 372: 2521–2532. DOI: 10.1056/NEJMoa1503093.

61. Kambayashi Y., Fujimura T., Hidaka T., Aiba S. Biomarkers for Predicting Efficacies of Anti-PD1 Antibodies. Front. Med. 2019; 6: 174. DOI: 10.3389/fmed.2019.00174.

62. Cho S.Y., Lipson E. J., Im H. J., Rowe S.P., Gonzalez E.M., Blackford A., Chirindel A., Pardoll D. M., Topalian S. L., Wahl R. L. Prediction of response to immune checkpoint inhibitor therapy using early-time-point 18F-FDG PET/CT imaging in patients with advanced melanoma. J. Nucl. Med. 2017; 58: 1421–1428. DOI: 10.2967/jnumed.116.188839.

63. Tan A.C., Emmett L., Lo S., Liu V., Kapoor R., Carlino M.S., Guminski A.D., Long G.V., Menzies A.M. FDG-PET response and outcome from anti-PD-1 therapy in metastatic melanoma. Ann. Oncol. 2018; 29: 2115–2120. DOI: 10.1093/annonc/mdy330.

64. Kythreotou A., Siddique A., Mauri F.A., Bower M., Pinato D. J. PD-L1. J. Clin. Pathol. 2018; 71: 189–194. DOI: 10.1136/jclinpath-2017–204853.

65. Zhou J., Mahoney K.M., Giobbie-Hurder A., Zhao F., Lee S., Liao X., Rodig S., Li J., Wu X., Butterfield L.H., et al. Soluble PD-L1 as a biomarker in malignant melanoma treated with checkpoint blockade. Cancer Immunol. Res. 2017; 5: 480–492. DOI: 10.1158/2326–6066.CIR-16–0329.

66. Cordonnier M., Nardin C., Chanteloup G., Derangere V., Algros M.P., Arnould L., Garrido C., Aubin F., Gobbo J. Tracking the evolution of circulating exosomal-PD-L1 to monitor melanoma patients. J. Extracell. Vesicles. 2020; 9: 1710899. DOI: 10.1080/20013078.2019.1710899.

67. Chen G., Huang A.C., Zhang W., Zhang G., Wu M., Xu W., Yu Z., Yang J., Wang B., Sun H., et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018; 560: 382–386. DOI: 10.1038/s41586–018–0392–8.

68. Del Re M., Marconcini R., Pasquini G., Rofi E., Vivaldi C., Bloise F., Restante G., Arrigoni E., Caparello C., Bianco M.G., et al. PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC. Br. J. Cancer. 2018; 118: 820–824. DOI: 10.1038/bjc.2018.9.

69. Sanmamed M. F., Perez-Gracia J.L., Schalper K.A., Fusco J.P., Gonzalez A., Rodriguez-Ruiz M.E., Oñate C., Perez G., Alfaro C., Martín-Algarra S., et al. 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: 1988–1995. DOI: 10.1093/annonc/mdx190.

70. Chow M. T., Ozga A.J., Servis R.L., Frederick D. T., Lo J.A., Fisher D.E., Freeman G.J., Boland G.M., Luster A.D. Intratumoral Activity of the CXCR3 Chemokine System Is Required for the Efficacy of Anti-PD-1 Therapy. Immunity. 2019; 50: 1498–1512. DOI: 10.1016/j.immuni.2019.04.010.

71. Erdag G., Schaefer J. T., Smolkin M.E., Deacon D.H., Shea S.M., Dengel L. T., Patterson J.W., Slingluff C. L. Immunotype and immunohistologic characteristics of tumor-infiltrating immune cells are associated with clinical outcome in metastatic melanoma. Cancer Res. 2012; 72: 1070–1080.

72. Fridman W.H., Pagès F., Sautès-Fridman C., Galon J. The immune contexture in human tumours: Impact on clinical outcome. Nat. Rev. Cancer. 2012; 12: 298–306. DOI: 10.1038/nrc3245.

73. Antohe M., Nedelcu R.I., Nichita L., Popp C.G., Cioplea M., Brinzea A., Hodorogea A., Calinescu A., Balaban M., Ion D.A., et al. Tumor infiltrating lymphocytes: The regulator of melanoma evolution (Review) Oncol. Lett. 2019; 17: 4155–4161. DOI: 10.3892/ol.2019.9940.

74. Taube J.M., Anders R.A., Young G.D., Xu H., Sharma R., McMiller T.L., Chen S., Klein A.P., Pardoll D.M., Topalian S. L., et al. Colocalization of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med. 2012; 4: 127ra37. DOI: 10.1126/scitranslmed.3003689.