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Research paper

Tumor-Infiltrating Lymphocytes and Breast Cancer: Are Immune Checkpoint Inhibitors Ready for Prime Time in Breast Cancer?

By
Ana Cvetanović ,
Ana Cvetanović
Slađana Filipović ,
Slađana Filipović
Nikola Živković ,
Nikola Živković
Miloš Kostić ,
Miloš Kostić
Svetislav Vrbić ,
Svetislav Vrbić
Ivica Pejčić
Ivica Pejčić

Abstract

SummaryIn recent years, results obtained from different studies with large cohorts have revealed a bond between the presence of extensive lymphocytic infiltration and favourable prognostic associations in the early-stage of breast cancer (BC) and high response rates to neoadjuvant chemotherapy. Examiners used tumors from large cohorts of patients who took part in randomized neoadjuvant and adjuvant clinical trials. The importance of tumor infiltrating lymphocytes (TILs) appears to be subtype-specific and varies depending on the histological characteristics of the tumor. TILs have proven to be a good prognostic marker, but only in highly proliferative breast tumors such as triple negative breast tumors (TNBC) or HER 2 positive BC.In the era when standard, well-known, prognostic and predictive biomarkers are ever changing and the use of molecular profiling analyses are increasing, we are looking for techniques to improve our understanding of tumor biology and improve patient outcome. The relevance of TILs cannot be ignored but needs to be properly evaluated in larger prospective studies which must encompass the parameters set out in previous studies. The use of TILs as prognostic biomarkers in early breast cancer may represent a new dawn, and use of immunotherapy, especially immune checkpoint inhibitors, probably is the future for the breast cancer but it is not yet ready for prime time.

References

1.
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Medicine. 2004;10(9):942–9.
2.
Mieog S, van der Hage J, van de Velde C. Preoperative chemotherapy for women with operable breast cancer. Cochrane Database of Systematic Reviews.
3.
Yu P, Fu YX. Tumor-infiltrating T lymphocytes: friends or foes? Laboratory Investigation. 2006;86(3):231–45.
4.
Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Annals of Oncology. 2015;26(2):259–71.
5.
Lee AHS, Gillett CE, Ryder K, Fentiman IS, Miles DW, Millis RR. Different patterns of inflammation and prognosis in invasive carcinoma of the breast. Histopathology. 2006;48(6):692–701.
6.
Muenst S, Soysal SD, Gao F, Obermann EC, Oertli D, Gillanders WE. The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Research and Treatment. 2013;139(3):667–76.
7.
Richardson WW. Medullary Carcinoma of the Breast. British Journal of Cancer. 1956;10(3):415–23.
8.
Aaltomaa S, Lipponen P, Eskelinen M, Kosma VM, Marin S, Alhava E, et al. Lymphocyte infiltrates as a prognostic variable in female breast cancer. European Journal of Cancer. 1992;28(4–5):859–64.
9.
Francis P, Crown J, Di Leo A, Buyse M, Balil A, Andersson M, et al. Adjuvant Chemotherapy With Sequential or Concurrent Anthracycline and Docetaxel: Breast International Group 02 98 Randomized Trial. JNCI Journal of the National Cancer Institute. 2008;100(2):121–33.
10.
Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. Journal of Clinical Oncology. 1998;16(8):2672–85.
11.
Zitvogel L, Kepp O, Kroemer G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nature Reviews Clinical Oncology. 2011;8(3):151–60.
12.
Mahmoud SMA, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AHS, et al. Tumor-Infiltrating CD8+Lymphocytes Predict Clinical Outcome in Breast Cancer. Journal of Clinical Oncology. 2011;29(15):1949–55.
13.
Desmedt C, Haibe-Kains B, Wirapati P, Buyse M, Larsimont D, Bontempi G, et al. Biological Processes Associated with Breast Cancer Clinical Outcome Depend on the Molecular Subtypes. Clinical Cancer Research. 2008;14(16):5158–65.
14.
Denkert C, Loibl S, Salat C, Sinn B, Schem C, Endris V, et al. Abstract S1-06: Increased tumor-associated lymphocytes predict benefit from addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer in the GeparSixto trial (GBG 66). Cancer Research. 2013;73(24_Supplement):S1-06-S1-06.
15.
Issa-Nummer Y, Darb-Esfahani S, Loibl S, Kunz G, Nekljudova V, Schrader I, et al. Prospective Validation of Immunological Infiltrate for Prediction of Response to Neoadjuvant Chemotherapy in HER2-Negative Breast Cancer – A Substudy of the Neoadjuvant GeparQuinto Trial. PLoS ONE. 8(12):e79775.
16.
Tumor Infiltrating Lymphocytes – The Next Step in Assessing Outcome and Response to Treatment in Patients with Breast Cancer. Journal of Carcinogenesis & Mutagenesis. 05(06).
17.
Alexe G, Dalgin GS, Scanfeld D, Tamayo P, Mesirov JP, DeLisi C, et al. High Expression of Lymphocyte-Associated Genes in Node-Negative HER2+ Breast Cancers Correlates with Lower Recurrence Rates. Cancer Research. 2007;67(22):10669–76.
18.
Sun S, Fei X, Mao Y, Wang X, Garfield DH, Huang O, et al. PD-1+ immune cell infiltration inversely correlates with survival of operable breast cancer patients. Cancer Immunology, Immunotherapy. 2014;63(4):395–406.
19.
Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. Intraepithelial CD8+tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proceedings of the National Academy of Sciences. 2005;102(51):18538–43.
20.
Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, 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. Annals of Oncology. 2014;25(8):1544–50.
21.
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome. Science. 2006;313(5795):1960–4.
22.
Denkert C, Loibl S, Noske A, Roller M, Müller BM, Komor M, et al. Tumor-Associated Lymphocytes As an Independent Predictor of Response to Neoadjuvant Chemotherapy in Breast Cancer. Journal of Clinical Oncology. 2010;28(1):105–13.
23.
Lee HJ, Seo JY, Ahn JH, Ahn SH, Gong G. Tumor-Associated Lymphocytes Predict Response to Neoadjuvant Chemotherapy in Breast Cancer Patients. Journal of Breast Cancer. 2013;16(1):32.
24.
Ma C, Zhang Q, Ye J, Wang F, Zhang Y, Wevers E, et al. Tumor-Infiltrating γδ T Lymphocytes Predict Clinical Outcome in Human Breast Cancer. The Journal of Immunology. 2012;189(10):5029–36.
25.
Oda N, Shimazu K, Naoi Y, Morimoto K, Shimomura A, Shimoda M, et al. Intratumoral regulatory T cells as an independent predictive factor for pathological complete response to neoadjuvant paclitaxel followed by 5-FU/epirubicin/cyclophosphamide in breast cancer patients. Breast Cancer Research and Treatment. 2012;136(1):107–16.
26.
Trzonkowski P, Szmit E, Myśliwska J, Dobyszuk A, Myśliwski A. CD4+CD25+ T regulatory cells inhibit cytotoxic activity of T CD8+ and NK lymphocytes in the direct cell-to-cell interaction. Clinical Immunology. 2004;112(3):258–67.
27.
Hornychová H, Melichar B, Tomšová M, Mergancová J, Urminská H, Ryška A. Tumor-Infiltrating Lymphocytes Predict Response to Neoadjuvant Chemotherapy in Patients with Breast Carcinoma. Cancer Investigation. 2008;26(10):1024–31.
28.
Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, et al. Preoperative Chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. Journal of Clinical Oncology. 2008;26(5):778–85.
29.
Rakha EA, Aleskandarany M, El-Sayed ME, Blamey RW, Elston CW, Ellis IO, et al. The prognostic significance of inflammation and medullary histological type in invasive carcinoma of the breast. European Journal of Cancer. 2009;45(10):1780–7.
30.
Murakami M, Sakamoto A, Bender J, Kappler J, Marrack P. CD25+CD4+ T cells contribute to the control of memory CD8+ T cells. Proceedings of the National Academy of Sciences. 2002;99(13):8832–7.
31.
Yamaguchi R, Tanaka M, Yano A, Tse GM, Yamaguchi M, Koura K, et al. Tumor-infiltrating lymphocytes are important pathologic predictors for neoadjuvant chemotherapy in patients with breast cancer. Human Pathology. 2012;43(10):1688–94.
32.
Leffers N, Gooden MJM, de Jong RA, Hoogeboom BN, ten Hoor KA, Hollema H, et al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunology, Immunotherapy. 2009;58(3):449–59.
33.
Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Abstract S1-05: Tumor infiltrating lymphocytes (TILs) indicate trastuzumab benefit in early-stage HER2-positive breast cancer (HER2+ BC). Cancer Research. 2013;73(24_Supplement):S1-05-S1-05.
34.
Beatty GL, Paterson Y. IFN-γ-Dependent Inhibition of Tumor Angiogenesis by Tumor-Infiltrating CD4+ T Cells Requires Tumor Responsiveness to IFN-γ. The Journal of Immunology. 2001;166(4):2276–82.
35.
Disis ML. Immune Regulation of Cancer. Journal of Clinical Oncology. 2010;28(29):4531–8.
36.
Boon T, Coulie PG, Van den Eynde B. Tumor antigens recognized by T cells. Immunology Today. 1997;18(6):267–8.
37.
Denkert C, Sinn BV, Issa Y, Müller BM, Maisch A, Untch M, et al. Prediction of Response to Neoadjuvant Chemotherapy: New Biomarker Approaches and Concepts. Breast Care. 2011;6(4):265–72.
38.
Perez EA, Thompson EA, Anderson SK, Asmann YW, Kalari KR, Eckel-Passow J, et al. Association of genomic analysis of immune function genes and clinical outcome in the NCCTG (Alliance) N9831 adjuvant trastuzumab trial. Journal of Clinical Oncology. 2014;32(15_suppl):509–509.
39.
Gianni L, Bianchini G, Valagussa P, Belousov A, Thomas M, Ross G, et al. Abstract S6-7: Adaptive immune system and immune checkpoints are associated with response to pertuzumab (P) and trastuzumab (H) in the NeoSphere study. Cancer Research. 2012;72(24_Supplement):S6-7-S6-7.
40.
Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, et al. Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nature Medicine. 2007;13(9):1050–9.
41.
Sharma P, Shen Y, Wen S, Yamada S, Jungbluth AA, Gnjatic S, et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proceedings of the National Academy of Sciences. 2007;104(10):3967–72.
42.
Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer. New England Journal of Medicine. 2003;348(3):203–13.
43.
Seo AN, Lee HJ, Kim EJ, Kim HJ, Jang MH, Lee HE, et al. Tumour-infiltrating CD8+ lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. British Journal of Cancer. 2013;109(10):2705–13.
44.
Smith IC, Heys SD, Hutcheon AW, Miller ID, Payne S, Gilbert FJ, et al. Neoadjuvant Chemotherapy in Breast Cancer: Significantly Enhanced Response With Docetaxel. Journal of Clinical Oncology. 2002;20(6):1456–66.
45.
Ono M, Tsuda H, Shimizu C, Yamamoto S, Shibata T, Yamamoto H, et al. Tumor-infiltrating lymphocytes are correlated with response to neoadjuvant chemotherapy in triple-negative breast cancer. Breast Cancer Research and Treatment. 2012;132(3):793–805.
46.
Demir L, Yigit S, Ellidokuz H, Erten C, Somali I, Kucukzeybek Y, et al. Predictive and prognostic factors in locally advanced breast cancer: effect of intratumoral FOXP3+ Tregs. Clinical & Experimental Metastasis. 2013;30(8):1047–62.

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