КЛЕТОЧНЫЙ ИММУНИТЕТ ПРИ РАКЕ ЯИЧНИКОВ

DOI: https://doi.org/10.29296/25877313-2019-01-01
Номер журнала: 
1
Год издания: 
2019

А.И. Черткова к.м.н., ст. науч. сотрудник, лаборатория клинической иммунологии опухолей, Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина (Москва) E-mail: antcher@gmail.com З.Г. Кадагидзе д.м.н., профессор, вед. науч. сотрудник, лаборатория клинической иммунологии опухолей, Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина (Москва) Т.Н. Заботина д.б.н., зав. централизованным клинико-лабораторным отделом, Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина (Москва) Н.Е. Кушлинский д.м.н., профессор, член-корр. РАН, руководитель лаборатории клинической биохимии, Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина (Москва)

Показано, что циторедуктивная хирургия и химиотерапия больных раком яичников (РЯ) обеспечивают ремиссию более чем в половине случаев. Однако у подавляющего числа больных с генерализованным процессом после лечения наступает рецидив заболевания, что указывает на необхо-димость введения новых методов лечения РЯ. Значительную роль в контроле опухолевого роста играет иммунная система. Рассматривается про-блема функционирования иммунной системы при раке яичников. Главное внимание уделяется популяциям эффекторных и регуляторных клеток, ин-фильтрирующих опухолевую ткань. Представленные литературные данные свидетельствуют о наличии противоопухолевого иммунного ответа у больных РЯ. Отмечено прогностическое значение иммунных клеток различного происхождения (Т-клетки-эффекторы, регуляторные Т-клетки, B-клетки, опухолеассоциированные макрофаги, миелоидные клетки-супрессоры) в клиническом течении заболевания.

Ключевые слова: 
рак яичников
лимфоциты
инфильтрирующие опухоль
эффекторные и регуляторные иммунные клетки

Список литературы: 
  1. Tse B.W., Collins A., Oehler M.K., Zippelius A., Heinzelmann-Schwarz V.A. Antibody-based immunotherapy for ovarian cancer: where are we at? Ann. Oncol. 2014; 25(2):322-331. doi: 10.1093/annonc/mdt405.
  2. Weidle U.H., Birzele F., Kollmorgen G., Rueger R. Mechanisms and targets involved in dissemination of ovarian cancer. Cancer Genomics Proteomics. 2016 11-12; 13(6):407-423. PMID: 27807064.
  3. Wei W., Giulia .1, Luffer S., Kumar R., Wu B., Tavallai M., Bekele R.T., Birrer M.J. How can molecular abnormalities influence our clinical approach. Ann. Oncol. 2017; 28(suppl_8):viii16-viii24. doi: 10.1093/annonc/mdx447.
  4. Hoppenot C., Eckert M.A., Tienda S.M., Lengyel E. Who are the long-term survivors of high grade serous ovarian cancer? Gynecol. Oncol. 2018; 148(1):204-212. doi: 10.1016/j.ygyno.2017.10.032.
  5. Quigley D.A., Kristensen V. Predicting prognosis and therapeutic response from interactions between lymphocytes and tumor cells. Mol. Oncol. 2015; 9(10): 2054-2062. doi: 10.1016/j.molonc.2015.10.003.
  6. Senovilla L., Galluzzi L., Zitvogel L., Kroemer G. Immunosurveillance as a regulator of tissue homeostasis. Trends Immunol. 2013; 34(10):471-481. doi: 10.1016/j.it.2013.06.005.
  7. Gubin M.M., Artyomov M.N., Mardis E.R., Schreiber R.D. Tumor neoantigens: building a framework for personalized cancer immunotherapy. J. Clin. Invest. 2015; 125(9):3413-3421.
  8. Olivera J. Finn Human Tumor Antigens Yesterday, Today, and Tomorrow Cancer Immunol Res. Author manuscript; available in PMC 2018 Cancer Immunol. Res. 2017;5(5):347-354. doi: 10.1158/2326-6066.CIR-17-0112.
  9. Кадагидзе З.Г., Черткова А.И. Иммунная система и рак. Практическая онкология. 2016; 17(2):62-73. http://www.practical-oncology.ru (Kadagidze Z.G., CHertkova A.I. Immunnaya sistema i rak. Prakticheskaya onkologiya. 2016; 17(2):62-73. http://www.practical-oncology.ru).
  10. Кадагидзе З.Г., Черткова А.И. Новые подходы к повышению эффективности противоопухолевого иммунного ответа. Иммунология. 2015; 36(1):66-70 (Kadagidze Z.G., CHertkova A.I. Novye podhody k povy-sheniyu ehffektivnosti protivoopuholevogo immunnogo otveta. Immunologiya. 2015; 36(1):66-70).
  11. Töpfer K., Kempe S., Müller N., Schmitz M., Bachmann M., Cartellieri M., Schackert G., Temme A. Tumor evasion from T cell surveillance. J. Biomed. Biotechnol. 2011; 2011:918471. doi: 10.1155/2011/918471.
  12. Chen D.S., Mellman I. Oncology meets immunology: the cancer-immunity cycle Immunity. 2013; 39(1):1-10. doi: 10.1016/j.immuni.2013.07.012.
  13. Lippitz B.E. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 2013;14(6):e218-e228. doi: 10.1016/S1470-2045(12)70582-X.
  14. Hornyák L., Dobos N., Koncz G., Karányi Z., Páll D., Sza-
  15. bó Z., Halmos G., Székvölgyi L. The Role of Indoleamine-2,3-dioxygenase in cancer development, diagnostics, and therapy. Front. Immunol. 2018; 9:151. doi: 10.3389/fimmu.2018.00151.
  16. Zhang L., Conejo-Garcia J.R., Katsaros D., Gimotty P.A., Massobrio M., Regnani G., Makrigiannakis A., Gray H., Schlienger K., Liebman M.N., Rubin S.C., Coukos G. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 2003; 348(3):203-213. PMID: 12529460.
  17. Galon J., Costes A., Sanchez-Cabo F., Kirilovsky A., Mlecnik B., Lagorce-Pages C., Tosolini M., Camus M., Berger A., Wind P., Zinzindohoue F., Bruneval P., Cugnenc P.H., Trajanoski Z., Fridman W.H., Pages F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006; 313:1960-1964. doi: 10.1126/science.1129139
  18. Geng Y., Shao Y., He W., Hu W., Xu Y., Chen J., Wu C., Jiang J. Prognostic role of tumor-infiltrating lymphocytes in lung cancer: a Meta-Analysis. Cell Physiol. Biochem. 2015; 37(4):1560-1571. doi: 10.1159/000438523.
  19. Bense R.D., Sotiriou C., Piccart-Gebhart M.J., Haanen J.B., van Vugt M.A., de Vries E.G., Schröder C.P., Fehrmann R.S. Relevance of tumor-infiltrating immune cell composition and functionality for disease outcome in breast cancer. J. Natl. Cancer Inst. 2016; 109(1).pii: djw192. doi: 10.1093/jnci/djw192.
  20. Wang K., Xu J., Zhang T., Xue D. Tumor-infiltrating lymphocytes in breast cancer predict the response to chemotherapy and survival outcome: A meta-analysis. Oncotarget. 2016; 7(28):44288-44298. doi: 10.18632/oncotarget.9988.
  21. Li J., Wang J., Chen R., Bai Y., Lu X. The prognostic value of tumor-infiltrating T lymphocytes in ovarian cancer. Oncotarget. 2017; 8(9):15621-15631. doi: 10.18632/oncotarget.14919.
  22. Komdeur F.L., Prins T.M., van de Wall S., Plat A., Wisman G.B.A., Hollema H., Daemen T., Church D.N., de Bruyn M., Nijman H.W. CD103+ tumor-infiltrating lymphocytes are tumor-reactive intraepithelial CD8+ T cells associated with prognostic benefit and therapy response in cervical cancer. Oncoimmunology. 2017; 6(9):e1338230. doi: 10.1080/2162402X.2017.1338230.
  23. Yu P.C., Long D., Liao C.C., Zhang S. Association between density of tumor-infiltrating lymphocytes and prognoses of patients with gastric cancer. Medicine (Baltimore). 2018; 97(27):e11387. doi: 10.1097/MD.0000000000011387.
  24. Zheng X., Song X., Shao Y., Xu B., Hu W., Zhou Q., Chen L., Zhang D., Wu C., Jiang J. Prognostic role of tumor-infilt-rating lymphocytes in esophagus cancer: a Meta-Analysis. Cell Physiol. Biochem. 2018; 45(2):720-732. doi: 10.1159/000487164.
  25. Ali-Fehmi R., Chatterjee M., Ionan A., Levin N.K., Arabi H., Bandyopadhyay S., Shah J.P., Bryant C.S., Hewitt S.M., O'Rand M.G., Alekseev O.M., Morris R., Munkarah A., Abrams J., Tainsky M.A. Analysis of the expression of human tumor antigens in ovarian cancer tissues Cancer Biomark. 2010; 6(1):33-48. doi: 10.3233/CBM-2009-0117.
  26. Matsuzaki J., Gnjatic S., Mhawech-Fauceglia P., Beck A., Miller A., Tsuji T., Eppolito C., Qian F., Lele S., Shrikant P., Old L.J., Odunsi K. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc. Natl. Acad. Sci. U S A. 2010; 107(17):7875-7880. doi: 10.1073/pnas.1003345107.
  27. Ma D., Gu M.J. Immune effect of tumor-infiltrating lymphocytes and its relation to the survival rate of patients with ovarian malignancies. J. Tongji Med. Univ. 1991; 11(4):235-239.
  28. Negus R.P., Stamp G.W., Hadley J., Balkwill F.R. Quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of C-C chemokines. Am. J. Pathol. 1997; 150(5):1723-1734. PMID: 9137096
  29. Santin A.D., Hermonat P.L., Ravaggi A., Bellone S., Roman J.J., Smith C.V., Pecorelli S., Radominska-Pandya A., Cannon M.J., Parham G.P. Phenotypic and functional analysis
  30. of tumor-infiltrating lymphocytes compared with tumor associated lymphocytes from ascitic fluid and peripheral blood lymphocytes in patients with advanced ovarian cancer.
  31. Gynecol. Obstet. Invest. 2001; 51(4):254-261. doi:10.1159/000058060.
  32. Raspollini M.R., Castiglione F., Rossi Degl'innocenti D., Amunni G., Villanucci A., Garbini F., Baroni G., Taddei G.L. Tumour-infiltrating gamma/delta T-lymphocytes are correlated with a brief disease-free interval in advanced ovarian serous carcinoma. Ann. Oncol. 2005; 16(4):590-596. doi: 10.1093/annonc/mdi112.
  33. Tomsová M., Melichar B., Sedláková I., Steiner I. Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma. Gynecol. Oncol. 2008; 108(2):415-420. DOI: 10.1016/j.ygyno.2007.10.016.
  34. Clarke B., Tinker A.V., Lee C.H., Subramanian S., van de Rijn M., Turbin D., Kalloger S., Han G., Ceballos K., Cadungog M.G., Huntsman D.G., Coukos G., Gilks C.B. Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss. Mod. Pathol. 2009; 22(3):393-402. doi:10.1038/modpathol.2008.191.
  35. Bösmüller H.C., Wagner P., Peper J.K., Schuster H., Pham D.L., Greif K., Beschorner C., Rammensee H.G., Stevanović S., Fend F., Staebler A. Combined immunoscore of CD103 and CD3 identifies iong-ierm survivors in high-grade serous ovarian cancer. Int. J. Gynecol. Cancer. 2016; 26(4):671-679. doi: 10.1097/IGC.0000000000000672.
  36. Strickland K.C., Howitt B.E., Shukla S.A., Rodig S., Ritterhouse L.L, Liu J.F., Garber J.E., Chowdhury D., Wu C.J., D'Andrea A.D., Matulonis U.A., Konstantinopoulos P.A. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget. 2016; 7(12):13587-13598. doi:10.18632/oncotarget.7277.
  37. Sato E., Olson S.H., Ahn J., Bundy B., Nishikawa H., Qian F., Jungbluth A.A., Frosina D., Gnjatic S., Ambrosone C., Kepner J., Odunsi T., Ritter G., Lele S., Chen Y.T., Ohtani H., Old L.J, Odunsi K. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc. Natl. Acad. Sci. U S A. 2005; 102(51):18538-18543. doi:10.1073/pnas.0509182102.
  38. Adams S.F., Levine D.A., Cadungog M.G., Hammond R., Facciabene A., Olvera N., Rubin S.C., Boyd J., Gimotty P.A., Coukos G. Intraepithelial T cells and tumor proliferation: impact on the benefit from surgical cytoreduction in advanced serous ovarian cancer. Cancer. 2009; 115(13):2891-2902. doi: 10.1002/cncr.24317.
  39. Strasser A., Jost P.J., Nagata S. The many roles of FAS receptor signaling in the immune system. Immunity. 2009; 30(2):180-192. doi: 10.1016/j.immuni.2009.01.001.
  40. Page`s F.K.A., Mlecnik B., Asslaber M., Tosolini M., Bindea G., Lagorce C., Wind P., Marliot F., Bruneval P., Zatloukal K., Trajanoski Z., Berger A., Fridman W.H., Galon J. In situ cytotoxic and memory T cells predict outcome in patients with early stage colorectal cancer. J. Clin. Oncol. 2009; 27(35):5944-5951. doi: 10.1200/JCO.2008.19.6147.
  41. Gooden M.J.M., de Bock G.H., Leffers N., Daemen T., Nijman H.W. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br. J. Cancer. 2011; 105(1):93-103. doi: 10.1038/bjc.2011.189.
  42. Senovilla L., Vacchelli E., Galon J., Adjemian S., Eggermont A., Fridman W.H., Sautès-Fridman C., Ma Y., Tartour E., Zitvogel L., Kroemer G., Galluzzi L. Trial watch: Prognostic and predictive value of the immune infiltrate in cancer. Oncoimmunology. 2012; 1(8):1323-1343. doi: 10.4161/onci.22009.
  43. Bachmayr-Heyda A., Aust S., Heinze G., Polterauer S., Grimm C., Braicu E.I., Sehouli J., Lambrechts S., Vergote I., Mahner S., Pils D., Schuster E., Thalhammer T., Horvat R., Denkert C., Zeillinger R., Castillo-Tong D.C. Prognostic impact of tumor infiltrating CD8+ T cells in association with cell proliferation in ovarian cancer patients - a study of the OVCAD consortium. BMC Cancer. 2013; 13:422. doi: 10.1186/1471-2407-13-422.
  44. Yu X., Zhang Z., Wang Z., Wu P., Qiu F., Huang J. Prognostic and predictive value of tumor-infiltrating lymphocytes in breast cancer: a systematic review and meta-analysis. Clin. Transl. Oncol. 2016; 18(5):497-506. doi: 10.1007/s12094-015-1391-y.
  45. Burugu S., Asleh-Aburaya K., Nielsen T.O. Immune infiltrates in the breast cancer microenvironment: detection, characterization and clinical implication. Breast Cancer. 2017; 24(1):3-15. doi: 10.1007/s12282-016-0698-z.
  46. Ovarian Tumor Tissue Analysis (OTTA) Consortium, Goode E.L., Block M.S., Kalli K.R., Vierkant R.A., Chen W., Fogarty Z.C., Gentry-Maharaj A., Tołoczko A., Hein A., Bouligny A.L., Jensen A., Osorio A., Hartkopf A., Ryan A., Chudecka-Głaz A., Magliocco A.M., Hartmann A., Jung A.Y., Gao B., Hernandez B.Y., Fridley B.L., McCauley B.M., Kennedy C.J., Wang C., Karpinskyj C., de Sousa C.B., Tiezzi D.G., Wachter D.L., Herpel E., Taran F.A., Modugno F., Nelson G., Lubiński J., Menkiszak J., Alsop J., Lester J., García-Donas J., Nation J., Hung., Palacios J., Rothstein J.H., Kelley J.L., de Andrade J.M., Robles-Díaz L., Intermaggio M.P., Widschwendter M., Beckmann M.W., Ruebner M., Jimenez-Linan M., Singh N., Oszurek O., Harnett P.R., Rambau P.F., Sinn P., Wagner P., Ghatage P., Sharma R., Edwards P., Ness R.B., Orsulic S., Brucker S.Y., Johnatty S.E., Longacre T.A., Ursula E., McGuire V., Sieh W., Natanzon Y., Li Z., Whittemore A.S., Anna A., Staebler A., Karlan B.Y., Gilks B., Bowtell D.D., Høgdall E., Candido dos Reis F.J., Steed H., Campbell I.G., Gronwald J., Benítez J., Koziak J.M., Chang-Claude J., Moysich K.B., Kelemen L.E., Cook L.S., Goodman M.T., García M.J., Fasching P.A., Kommoss S., Deen S., Kjaer S.K., Menon U., Brenton J.D., Pharoah P.D.P., Chenevix-Trench G., Huntsman D.G., Winham S.J., Köbel M., Ramus S.J. Dose-response association of CD8+ tumor-infiltrating lymphocytes and survival time in high-grade serous ovarian cancer. JAMA Oncol. 2017; 3(12):e173290. doi: 10.1001/jamaoncol.2017.3290.
  47. Santoiemma P.P., Reyes C., Wang L.P., McLane M.W., Feldman M.D., Tanyi J.L., Powell D.J.(Jr.) Systematic evaluation of multiple immune markers reveals prognostic factors in ovarian cancer. Gynecol. Oncol. 2016; 143(1):120-127. doi:10.1016/j.ygyno.2016.07.105.
  48. Redjimi N., Duperrier-Amouriaux K., Raimbaud I., Luescher I., Dojcinovic D., Classe J.M., Berton-Rigaud D., Frenel J.S., Bourbouloux E., Valmori D., Ayyoub M. NY-ESO-1-specific circulating CD4+T cells in ovarian cancer patients are prevalently T(H)1 type cells undetectable in the CD25+ FOXP3+ Treg compartment. PLoS One. 2011; 6(7):e22845. doi: 10.1371/journal.pone.0022845.
  49. Ayyoub M., Dojcinovic D., Pignon P., Raimbaud I., Schmidt J., Luescher I., Valmori D. Monitoring of NY-ESO-1 specific CD4+ T cells using molecularly defined MHC class II/His-tag-peptide tetramers. Proc. Natl. Acad. Sci. USA. 2010; 107(16):7437-7442. doi: 10.1073/pnas.1001322107.
  50. Ayyoub M., Pignon P., Classe J.M., Odunsi K., Valmori D. CD4+ T effectors specific for the tumor antigen NY-ESO-1 are highly enriched at ovarian cancer sites and coexist with, but are distinct from, tumor-associated Treg. Cancer Immunol Res. 2013; 1(5):303-308. doi: 10.1158/2326-6066.CIR-13-0062-T.
  51. Rodriguez G.M., Galpin K.J.C., McCloskey C.W., Vanderhyden B.C. The tumor microenvironment of epithelial ovarian cancer and its influence on response to immunotherapy. Cancers (Basel). 2018; 10(8). pii: E242. doi: 10.3390/cancers10080242.
  52. Valmori D., Ayyoub M. CD4+ T helper cell responses to NY-ESO-1 tumor antigen in ovarian cancer resist perversion into immunosuppressive Tregs. Oncoimmunology. 2014; 4(12):e946370. doi: 10.4161/21624011.2014.946370.
  53. Guy T.V., Terry A.M., Bolton H.A., Hancock D.G., Zhu E., Brink R., McGuire H.M., Shklovskaya E., Fazekas de St. Groth B. Collaboration between tumor-specific CD4+ T cells and B cells in anti-cancer immunity. Oncotarget. 2016; 7(21):30211-30229. doi: 10.18632/oncotarget.8797.
  54. Shen M., Wang J., Ren X. New insights into tumor-infiltrating B lymphocytes in breast cancer: clinical impacts and regulatory mechanisms. Front. Immunol. 2018; 9:470. doi: 10.3389/fimmu.2018.00470.
  55. Wang S.S., Liu W., Ly D., Xu H., Qu L., Zhang L. Tumor-infiltrating B cells: their role and application in anti-tumor immunity in lung cancer. Cell. Mol. Immunol. 2018; doi: 10.1038/s41423-018-0027-x.
  56. Nielsen J.S., Sahota R.A., Milne K., Kost S.E., Nesslinger N.J., Watson P.H., Nelson B.H. CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin. Cancer Res. 2012; 18(12):3281-3292. doi: 10.1158/1078-0432.CCR-12-0234.
  57. Schwartz M., Zhang Y., Rosenblatt J.D. B cell regulation of the anti-tumor response and role in carcinogenesis. J. Immunother. Cancer. 2016; 4:40. doi: 10.1186/s40425-016-0145-x.
  58. Sarvaria A., Madrigal J.A., Saudemont A. B cell regulation in cancer and anti-tumor immunity. Cell. Mol. Immunol. 2017; 14(8):662-674. doi: 10.1038/cmi.2017.35.
  59. Yang C., Lee H., Jove V., Deng J., Zhang W., Liu X., Forman S., Dellinger T.H., Wakabayashi M., Yu H., Pal S. Prognostic significance of B-cells and pSTAT3 in patients with ovarian cancer. PLoS One. 2013; 8(1):e54029. doi: 10.1371/journal.pone.0054029.
  60. Lundgren S., Berntsson J., Nodin B., Micke P., Jirström K. Prognostic impact of tumour-associated B cells and plasma cells in epithelial ovarian cancer. J. Ovarian Res. 2016; 9:21. doi: 10.1186/s13048-016-0232-0.
  61. Sakaguchi S., Sakaguchi N,, Asano M,, Itoh M,, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 1995; 155(3):1151-1164. PMID: 7636184.
  62. Sakaguchi S., Yamaguchi T., Nomura T., Ono M. Regulatory T cells and immune tolerance. Cell. 2008; 133(5):775-787. doi: 10.1016/j.cell.2008.05.009.
  63. Shitara K., Nishikawa H. Regulatory T cells: a potential target in cancer immunotherapy. Ann. NY Acad. Sci. 2018; 1417(1):104-115. doi: 10.1111/nyas.13625. Epub 2018 Mar.
  64. Mohr A., Malhotra R., Mayer G., Gorochov G., Miyara M. Human FOXP3+ T regulatory cell heterogeneity. Clin. Transl. Immunology. 2018; 7(1):e1005. doi: 10.1002/cti2.1005.
  65. Takeuchi Y., Nishikawa H. Roles of regulatory T cells in cancer immunity. Int. Immunol. 2016; 28(8):401-409. doi: 10.1093/intimm/dxw025.
  66. Curiel T.J., Coukos G., Zou L., Alvarez X., Cheng P., Mottram P., Evdemon-Hogan M., Conejo-Garcia J.R., Zhang L., Burow M., Zhu Y., Wei S., Kryczek I., Daniel B., Gordon A., Myers L., Lackner A., Disis M.L., Knutson K.L., Chen L., Zou W. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 2004; 10(9):942-949. doi: 10.1038/nm1093.
  67. Leffers N., Gooden M.J., de Jong R.A., Hoogeboom B.N., ten Hoor K.A., Hollema H., Boezen H.M., van der Zee A.G., Daemen T., Nijman H.W. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol. Immunother. 2009; 58(3):449-459. doi: 10.1007/s00262-008-0583-5.
  68. Zhu Q., Wu X., Wu Y., Wang X. Interaction between Treg cells and tumor-associated macrophages in the tumor microenvironment of epithelial ovarian cancer. Oncol Rep. 2016; 36(6):3472-3478. doi: 10.3892/or.2016.5136
  69. Ladoire S., Martin F., Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol. Immunother. 2011; 60(7):909-918. doi: 10.1007/s00262-011-1046-y.
  70. Badoual C., Hans S., Rodriguez J., Peyrard S., Klein C., Agueznay Nel H., Mosseri V., Laccourreye O., Bruneval P., Fridman W.H., Brasnu D.F., Tartour E. Prognostic value of tumorinfiltrating CD4(+) T-cell subpopulations in head and neck cancers. Clin. Cancer Res. 2006; 12(2):465-472. doi: 10.1158/1078-0432.CCR-05-1886.
  71. Zhang S., Ke X., Zeng S., Wu M., Lou J., Wu L., Huang P., Huang L., Wang F., Pan S. Analysis of CD8+ Treg cells in patients with ovarian cancer: A possible mechanism for immune impairment. Cell. Mol. Immunol. 2015; 12(5):580-591. doi: 10.1038/cmi.2015.57.
  72. Wu M., Chen X., Lou J., Zhang S., Zhang X., Huang L., Sun R., Huang P., Wang F., Pan S. TGF-β1 contributes to CD8+ Treg induction through p38 MAPK signaling in ovarian cancer microenvironment. Oncotarget. 2016; 7(28):44534-44544. doi: 10.18632/oncotarget.10003
  73. Colvin E.K. Tumor-associated macrophages contribute to tumor progression in ovarian cance. Front Oncol. 2014; 4:137. doi: 10.3389/fonc.2014.00137.
  74. Yuan X., Zhang J., Li D., Mao Y., Mo F., Du W., Ma X. Prognostic significance of tumor-associated macrophages in ovarian cancer: A meta-analysis. Gynecol. Oncol. 2017; 147(1):181-187. doi: 10.1016/j.ygyno.2017.07.007.
  75. Walankiewicz M., Grywalska E., Polak G., Kotarski J., Siwicka-Gieroba D.J., Roliński J. Myeloid-derived suppressor cells in ovarian cancer: friend or foe? Cent. Eur. J. Immunol. 2017; 42(4):383-389. doi: 10.5114/ceji.2017.72823