Tumor infiltrating lymphocytes: biological essence and clinical significance in breast cancer


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Abstract

In the review there are described the key stages of the development of anti-tumor immune response, as well there are presented the modern data on biological and clinical significance of tumor infiltrating lymphocytes in breast cancer; there is considered the method ofpathologic assessment of the pronouncement of lymphoid infiltration of the tumor; the results of clinical studies of prognostic and predictive role of immune markers including tumor infiltrating lymphocytes were analyzed.

About the authors

Marina B. Stenina

N.N. Blokhin Russian Cancer Research Center

Email: mstenina@mail.ru
MD., PhD, DSc., leading researcher Department of clinical pharmacology and chemotherapy of the Research Institute of Clinical Oncology Moscow, 115478, Russian Federation

E. V Tsareva

N.N. Blokhin Russian Cancer Research Center

Moscow, 115478, Russian Federation

A. A Zharov

N.N. Blokhin Russian Cancer Research Center

Moscow, 115478, Russian Federation

S. A Tyulyandin

N.N. Blokhin Russian Cancer Research Center

Moscow, 115478, Russian Federation

References

  1. Kim R., Emi M., Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology. 2007; 121: 1-14.
  2. Stewart T.J., Abrams S.I. How tumors escape mass destruction. Oncogene. 2008; 27: 5894-903.
  3. Li Q., Teitz-Tennenbaum S., Donald E.J. et al. In vivo sensitized and in vitro activated B cells mediate tumor regression in cancer adoptive immunotherapy. J. Immunol. 2009. 183: 3195-203.
  4. Nelson B.H. CD20+ B cells: the other tumor-infiltrating lymphocytes. J. Immunol. 2010; 185 (9): 4977-82.
  5. Manson L.A. Does antibody-dependent epitope masking permit progressive tumor growth in the face of cell-mediated cytotoxicity? Immunol. Today. 1991; 12: 352-5.
  6. Chen D.S., Mellman I. Oncology meets immunology: The cancerimmunity cycle. Immunity. 2013; 39: 1-10.
  7. Yannelli J.R., Hyatt C., McConnell S. et al. Growth of tumor-infiltrating lymphocytes from human solid cancers: summary of a 5-year experience. Int. J. Cancer. 1996: 65: 413-21.
  8. Rosenberg S.A., Spiess P., Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986; 233: 1318-21.
  9. Rosenberg S., Yang J., Sherry R. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 2011; 17 (13): 4550-7.
  10. Aaltomaa S., Lipponen P., Eskelinen M. et al. Lymphocyte infiltrates as a prognostic variable in female breast cancer. Eur. J. Cancer. 1992; 28A: 859-64.
  11. Loi S., Sirtaine N., Piette F. et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J. Clin. Oncol. 2013; 31: 860-7.
  12. Adams S., Demaria S., Goldstein L. et al. Prognostic value of tumorinfiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J. Clin. Oncol. 2014; 32: 2959-66.
  13. Loi S., Michiels S., Salgado R. et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann. Oncol. 2014; 25 (8): 1544-50.
  14. Артамонова Е.В. Роль иммунофенотипирования опухолевых клеток в диагностике и прогнозе рака молочной железы: Дисс. ... д-ра мед. наук. М.; 2003.
  15. Жукова Л.Г. Клинические и фундаментальные аспекты прогноза и рационального лечения рака молочной железы с тройным негативным фенотипом: Дисс. ... д-ра мед. наук. М.; 2015.
  16. West N.R., Kost S.E., Martin S.D. et al. Tumor-infiltrating FOXP3(+) lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer. Br. J. Cancer. 2013; 108 (1): 155-62.
  17. Yamaguchi R., Tanaka M., Yano A. et al. Tumor-infiltrating lymphocytes are important pathologic predictors for neoadjuvant chemotherapy in patients with breast cancer. Hum. Pathol. 2012; 43 (10): 1688-94.
  18. Lee S., Cho E.Y., Park Yh. et al. Prognostic impact of FOXP3 expression in triple-negative breast cancer. Acta Oncol. 2013; 52 (1): 73-81.
  19. Demir L., Yigit S., Ellidokuz H. et al. Predictive and prognostic factors in locally advanced breast cancer: effect of intratumoral FOXP3+ Tregs. Clin. Exp. Metastas. 2013; 30 (8): 1047-62.
  20. Melichar B., Študentova H., Kalábová H. et al. Predictive and prognostic significance of tumor-infiltrating lymphocytes in patients with breast cancer treated with neoadjuvant systemic therapy. Anticancer Res. 2014; 34 (3): 1115-25.
  21. Koh Y.W., Lee H.J., Ahn J.H. et al. Prognostic significance of the ratio of absolute neutrophil to lymphocyte counts for breast cancer patients with ER/PR positivity and HER2-negativity in neoadjuvant setting. Tumor Biol. 2014; 35 (10): 9823-30.
  22. Schatton T., Scolyer R.A., Thompson J.F. et al. Tumor-infiltrating lymphocytes and their significance in melanoma prognosis. Meth. Mol. Biol. 2014; 1102: 287-324.
  23. García-Martínez E., Gil G.L., Asunción Chaves Benito A.C. et al. Tumor-infiltrating immune cell profiles and their change after neoadjuvant chemotherapy predict response and prognosis of breast cancer. Breast Cancer Res. 2014; 16 (6): 488.
  24. Gu-Trantien C., Loi S., Garaud S. et al. CD4(+) follicular helper T cell infiltration predicts breast cancer survival. J. Clin. Invest. 2013; 123 (7): 2873-92.
  25. Emens L.A. Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade. Expert Rev. Anticancer Ther. 2012; 12 (12): 1597-611.
  26. Ali H.R., Provenzano E., Dawson S.J. et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12439 patients. Ann. Oncol. 2014; 25: 1536-43.
  27. Mahmoud S.M., Paish E.C., Powe D.G. et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J. Clin. Oncol. 2011; 29 (15): 1949-55.
  28. Mahmoud S., Lee A., Ellis I., Green A. CD8(+) T lymphocytes infiltrating breast cancer: A promising new prognostic marker? Oncoimmunology. 2012; 1 (3): 364-5.
  29. Godet Y. et al. Analysis of spontaneous tumor-specific CD4 T-cell immunity in lung cancer using promiscuous HLA-DR telomerase derived epitopes: potential synergistic effect with chemotherapy response. Clin. Cancer Res. 2012; 18 (10): 2943-53.
  30. Ruffell B., Au A., Rugo H.S. et al. Leukocyte composition of human breast cancer. Proc. Natl. Acad. Sci. USA. 2012; 109: 2796-801.
  31. Bos R., Marquardt K.L., Cheung J., Sherman L.A. Functional differences between low- and high-affinity CD8(+) T cells in the tumor environment. Oncoimmunology. 2012; 1 (8): 1239-47.
  32. Bos R., Sherman LA. CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes. Cancer Res. 2010; 70 (21): 8368-77.
  33. Faghih Z., Erfani N., Haghshenas M.R. et al. Immune profiles of CD4+ lymphocyte subsets in breast cancer tumor draining lymph nodes. Immunol. Lett. 2014; 158 (1-2): 57-65.
  34. Droeser R., Zlobec I., Kilic E. et al. Differential pattern and prognostic significance of CD4+, FOXP3+ and IL-17+ tumor infiltrating lymphocytes in ductal and lobular breast cancers. BMC Cancer. 2012; 12: 134.
  35. Gooden M.J.M., de Bock G.H., Leffers N. et al. The prognostic influence of tumor-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br. J. Cancer. 2011; 105 (1): 93-103.
  36. de Leeuw R.J., Kost S.E., Kakal J.A., Nelsonde B.H. The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin. Cancer Res. 2012; 18 (11): 3022-9.
  37. Tan W., Zhang W., Strasner A. et al. Fibroblast-recruited, tumor-infiltrating CD4+ T-cells stimulate mammary cancer metastasis through RANKL-RANK signaling. Nature. 2011; 470: 548-53.
  38. Bates G.J., Fox S.B., Han C. et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J. Clin. Oncol. 2006; 24: 5373-80.
  39. Ladoire S., Arnould L., Apetoh L. et al. Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating FOXP3+ regulatory T cells. Clin. Cancer Res. 2008; 14: 2413-20.
  40. Liu S., Lachapelle J., Leung S. et al. CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res. 2012; 14 (2): R48.
  41. Ono M., Tsuda H., Shimizu C. et al. Tumor-infiltrating lymphocytes are correlated with response to neoadjuvant chemotherapy in triplenegative breast cancer. Breast Cancer Res. Treat. 2012; 132 (3): 793-805.
  42. Krell J., Frampton A.E., Stebbing J. The clinical significance of tumor infiltrating lymphoctyes in breast cancer: does subtype matter? BMC Cancer. 2012; 12: 135-6.
  43. Loi S., Sirtaine N., Piette F. et al. Tumor-infiltrating lymphocytes, breast cancer subtypes and therapeutic efficacy. Oncoimmunology. 2013; 2 (7): e24720.
  44. Cimino-Mathews A., Ye X., Meeker A. et al. Metastatic triplenegative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: a pilot study. Hum. Pathol. 2013; 44 (10): 2055-63.
  45. Kim S.T., Jeong H., Woo O.H. et al. Tumor-infiltrating lymphocytes, tumor characteristics, and recurrence in patients with early breast cancer. Am. J. Clin. Oncol. 2013; 36 (3): 224-31.
  46. Jia Y., Xu L., Lin Q. et al. Levels of lymphocyte subsets in peripheral blood prior treatment are associated with aggressive breast cancer phenotypes or subtypes. Med. Oncol. 2014; 31 (6): 981.
  47. Martinet L., Filleron T., Guellec S.L. et al. High endothelial venule blood vessels for tumor-infiltrating lymphocytes are associated with lymphotoxin beta producing dendritic cells in human breast cancer. J. Immunol. 2013; 191: 2001-8.
  48. Nakakubo Y., Miyamoto M., Cho Y. et al. Clinical significance of immune cell infiltration within gallbladder cancer. Br. J. Cancer. 2003; 89: 1736-42.
  49. Gao Q., Qiu S.J., Fan J. et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J. Clin. Oncol. 2007; 25: 2586-93.
  50. Kobayashi N., Hiraoka N., Yamagami W. et al. FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin. Cancer Res. 2007; 13: 902-11.
  51. Tomsova M., Melichar B., Sedlakova I., Steiner I. Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma. Gynecol. Oncol. 2008; 108: 415-20.
  52. Zhang L., Conejo-Garcia J.R., Katsaros D. et al. Intratumoral T-cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 2003; 348: 203-13.
  53. Yamagami W., Susumu N., Tanaka H. et al. Immunofluorescencedetected infiltration of CD4+FOXP3+ regulatory Tcells is relevant to the prognosis of patients with endometrial cancer. Int. J. Gynecol. Cancer. 2011; 21: 1628-34.
  54. Ino K., Yamamoto E., Shibata K. et al. Inverse correlation between tumoral indoleamine-2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: Its association with disease progression and survival. Clin. Cancer Res. 2008; 14: 2310-7.
  55. Kondratiev S., Sabo E., Yakirevich E., Lavie O., Resnick M.B. Intratumoral CD8+ T lymphocytes as a prognostic factor of survival in endometrial carcinoma. Clin. Cancer Res. 2004; 10: 4450-6.
  56. de Jong R.A., Leffers H.M., ten Hoor K.A. et al. Presence of tumorinfiltrating lymphocytes is an independent prognosis factor in type I and II endometrial cancer. Gynecol. Oncol. 2009; 114: 105-10.
  57. Naito Y., Saito K., Shiiba K. et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998; 58 (16): 3491-4.
  58. Menon A.G., Janssen-Van Rhijn C.M., Morreau H. et al. Immune system and prognosis in colorectal cancer: a detailed immunohistochemical analysis. Lab. Invest. 2004; 84 (4): 493-501.
  59. Salgado R., Denkert C., Demaria S., Sirtaine N. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann. Oncol. 2015; 26: 259-71.
  60. Denkert C., von Minckwitz G., Brase J.C. et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J. Clin. Oncol. 2015; 33: 983-91.
  61. Denkert C., Loibl S., Noske A. et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J. Clin. Oncol. 2010; 28: 105-13.
  62. Mohammed Z., Going J.J., Edwards J. et al. The relationship between components of tumor inflammatory cell infiltrate and clinicopathological factors and survival in patients with primary operable invasive ductal breast cancer. Br. J. Cancer. 2012; 107: 864-73.
  63. Seo A.N., Lee H.J., Kim E.J. et al. Tumour-infiltrating CD8+ lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. Br. J. Cancer. 2013; 109: 2705-13.
  64. Zitvogel L., Kepp O., Kroemer G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat. Rev. Clin. Oncol. 2011; 8 (3): 151-60.
  65. Demaria S., Volm M.D., Shapiro R.L. et al. Development of tumorfiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin. Cancer Res. 2001; 7 (10): 3025-30.
  66. Tsavaris N., Kosmas C., Vadiaka M. et al. Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes. Br. J. Cancer. 2002; 87 (1): 21-7.
  67. Emens L.A., Asquith J.M., Leatherman J.M. et al. Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor-secreting breast tumor vaccine: a chemotherapy dose-ranging factorial study of safety and immune activation. J. Clin. Oncol. 2009; 27 (35): 5911-8.
  68. Andre F., Dieci M.V., Dubsky P. et al. Molecular Pathways: Involvement of Immune Pathways in the Therapeutic Response and Outcome in Breast Cancer. Clin. Cancer Res. 2013; 19 (1): 28-33.
  69. Ladoire S., Mignot G., Dabakuyo S. et al. In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J. Pathol. 2011; 224: 389-400.
  70. Hornychova H., Melichar B., Tomsova M. et al. Tumor-infiltrating lymphocytes predict response to neoadjuvant chemotherapy in patients with breast carcinoma. Cancer Invest. 2008; 26: 1024-31.
  71. Ignatiadis M., Singhal S.K., Desmedt C. et al. Gene modules and response to neoadjuvant chemotherapy in breast cancer subtypes: a pooled analysis. J. Clin. Oncol. 2012; 30: 1996-2004.
  72. Mao Y., Qu Q., Zhang Y. et al. The value of tumor infiltrating lymphocytes (TILs) for predicting response to neoadjuvant chemotherapy in breast cancer: A systematic review and meta-analysis. PLoS One. 2014; 9 (12): e115103.
  73. Gennari R., Menard S., Fagnoni F. et al. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin. Cancer Res. 2004; 10: 5650-5.
  74. Perez E.A., Thompson E.A., Ballman K.V. et al. Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group n9831 Adjuvant Trastuzumab Trial. J. Clin. Oncol. 2015; 33 (7): 701-8.
  75. Perez E.A., Ballman K.V., Anderson S.K. et al. Stromal tumor-infiltrating lymphocytes (S-TILs): In the alliance N9831 trial S-TILs are associated with chemotherapy benefit but not associated with trastuzumab benefit. In: San Antonio Breast Cancer Symposium. 2014: S1-06.
  76. Brahmer J.R., Tykodi S.S., Chow L.Q. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012; 366 (26): 2455-65.
  77. Taube J.M., Klein A., Brahmer J.R. et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 2014; 20 (19): 5064-74.
  78. Hamid O., Schmidt H., Nissan A. et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J. Transl. Med. 2011; 9: 204-19.

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