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The role of immune infiltrates as prognostic biomarkers in patients with breast cancer

Cancer Immunology, Immunotherapy volume 68, pages 1671–1680 (2019)Cite this article

Abstract

The presence of immune infiltrates in the tumor microenvironment has been documented in many types of cancer. Moreover, the preexistent or endogenous immunity which consists of interactions between intratumoral lymphocytes and tumor cells is mostly relevant for the successful application of various anticancer therapies, including standard chemotherapy, immune checkpoint inhibition-based immunotherapy and targeted therapies. The immunoscore defines densities of intratumoral immune infiltrates which determine poor or favorable prognosis depending on their quantity and quality in the tumor compartments. Results from large clinical studies have demonstrated an association between high densities of cytotoxic and memory TILs in the tumor compartments with improved prognosis. Importantly, we have demonstrated that differential combined densities of immune infiltrates jointly analyzed in the tumor center (TC) and the invasive margin (IM) have a significant prognostic value in breast cancer patients with poor clinicopathological parameters.

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Fig. 1

Abbreviations

BCa:

Breast cancer

CDK4/6:

Cyclin-dependent kinase 4 and 6

DFS:

Disease-free survival

ER:

Estrogen receptor

FCIS:

Favorable combined immune signature

HEV:

High endothelial venule

IM:

Invasive margin

TAM:

Tumor-associated macrophages

TC:

Tumor center

Th:

T-helper

TMB:

Tumor mutational burden

Tregs:

Regulatory T cells

UCIS:

Unfavorable combined immune signature

References

  1. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A (2017) Primary, Adaptive, and acquired resistance to cancer immunotherapy. Cell 168(4):707–723. https://doi.org/10.1016/j.cell.2017.01.017

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21(2):137–148. https://doi.org/10.1016/j.immuni.2004.07.017

    CAS  Article  PubMed  Google Scholar 

  3. Zhu J, Petit PF, Van den Eynde BJ (2018) Apoptosis of tumor-infiltrating T lymphocytes: a new immune checkpoint mechanism. Cancer Immunol Immunother. https://doi.org/10.1007/s00262-018-2269-y

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bindea G, Mlecnik B, Fridman WH, Pages F, Galon J (2010) Natural immunity to cancer in humans. Curr Opin Immunol 22(2):215–222. https://doi.org/10.1016/j.coi.2010.02.006

    CAS  Article  PubMed  Google Scholar 

  5. Spranger S (2016) Tumor heterogeneity and tumor immunity: a chicken-and-egg problem. Trends Immunol 37(6):349–351. https://doi.org/10.1016/j.it.2016.04.008

    CAS  Article  PubMed  Google Scholar 

  6. Fridman WH, Zitvogel L, Sautes-Fridman C, Kroemer G (2017) The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol 14(12):717–734. https://doi.org/10.1038/nrclinonc.2017.101

    CAS  Article  PubMed  Google Scholar 

  7. Baxevanis CN, Perez SA (2015) Cancer dormancy: a regulatory role for endogenous immunity in establishing and maintaining the tumor Dormant state. Vaccines (Basel) 3(3):597–619. https://doi.org/10.3390/vaccines3030597

    CAS  Article  Google Scholar 

  8. Vano YA, Petitprez F, Giraldo NA, Fridman WH, Sautes-Fridman C (2018) Immune-based identification of cancer patients at high risk of progression. Curr Opin Immunol 51:97–102. https://doi.org/10.1016/j.coi.2018.03.005

    CAS  Article  PubMed  Google Scholar 

  9. Church SE, Galon J (2017) Regulation of CTL infiltration within the tumor microenvironment. Adv Exp Med Biol 1036:33–49. https://doi.org/10.1007/978-3-319-67577-0_3

    CAS  Article  PubMed  Google Scholar 

  10. Fang D, Zhu J (2017) Dynamic balance between master transcription factors determines the fates and functions of CD4 T cell and innate lymphoid cell subsets. J Exp Med 214(7):1861–1876. https://doi.org/10.1084/jem.20170494

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Shang B, Liu Y, Jiang SJ, Liu Y (2015) Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep 5:15179. https://doi.org/10.1038/srep15179

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Whiteside TL (2014) Regulatory T cell subsets in human cancer: are they regulating for or against tumor progression? Cancer Immunol Immunother 63(1):67–72. https://doi.org/10.1007/s00262-013-1490-y

    CAS  Article  PubMed  Google Scholar 

  13. Whiteside TL (2015) The role of regulatory T cells in cancer immunology. Immunotargets Ther 4:159–171. https://doi.org/10.2147/ITT.S55415

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Shou J, Zhang Z, Lai Y, Chen Z, Huang J (2016) Worse outcome in breast cancer with higher tumor-infiltrating FOXP3+ Tregs: a systematic review and meta-analysis. BMC Cancer 16:687. https://doi.org/10.1186/s12885-016-2732-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Whiteside TL (2012) Disarming suppressor cells to improve immunotherapy. Cancer Immunol Immunother 61(2):283–288. https://doi.org/10.1007/s00262-011-1171-7

    CAS  Article  PubMed  Google Scholar 

  16. Asano Y, Kashiwagi S, Goto W, Kurata K, Noda S, Takashima T, Onoda N, Tanaka S, Ohsawa M, Hirakawa K (2016) Tumour-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to neoadjuvant chemotherapy of aggressive breast cancer. Br J Surg 103(7):845–854. https://doi.org/10.1002/bjs.10127

    CAS  Article  PubMed  Google Scholar 

  17. Miyashita M, Sasano H, Tamaki K, Chan M, Hirakawa H, Suzuki A, Tada H, Watanabe G, Nemoto N, Nakagawa S, Ishida T, Ohuchi N (2014) Tumor-infiltrating CD8+ and FOXP3+ lymphocytes in triple-negative breast cancer: its correlation with pathological complete response to neoadjuvant chemotherapy. Breast Cancer Res Treat 148(3):525–534. https://doi.org/10.1007/s10549-014-3197-y

    CAS  Article  PubMed  Google Scholar 

  18. Nabholtz JM, Abrial C, Mouret-Reynier MA, Dauplat MM, Weber B, Gligorov J, Forest AM, Tredan O, Vanlemmens L, Petit T, Guiu S, Van Praagh I, Jouannaud C, Dubray-Longeras P, Tubiana-Mathieu N, Benmammar KE, Kullab S, Bahadoor MR, Radosevic-Robin N, Kwiatkowski F, Desrichard A, Cayre A, Uhrhammer N, Chalabi N, Chollet P, Penault-Llorca F (2014) Multicentric neoadjuvant phase II study of panitumumab combined with an anthracycline/taxane-based chemotherapy in operable triple-negative breast cancer: identification of biologically defined signatures predicting treatment impact. Ann Oncol 25(8):1570–1577. https://doi.org/10.1093/annonc/mdu183

    CAS  Article  PubMed  Google Scholar 

  19. Chan MS, Wang L, Felizola SJ, Ueno T, Toi M, Loo W, Chow LW, Suzuki T, Sasano H (2012) Changes of tumor infiltrating lymphocyte subtypes before and after neoadjuvant endocrine therapy in estrogen receptor-positive breast cancer patients—an immunohistochemical study of Cd8+ and Foxp3+ using double immunostaining with correlation to the pathobiological response of the patients. Int J Biol Markers 27(4):e295–e304. https://doi.org/10.5301/JBM.2012.10439

    CAS  Article  PubMed  Google Scholar 

  20. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, Watkins TB, Shafi S, Murugaesu N, Mitter R, Akarca AU, Linares J, Marafioti T, Henry JY, Van Allen EM, Miao D, Schilling B, Schadendorf D, Garraway LA, Makarov V, Rizvi NA, Snyder A, Hellmann MD, Merghoub T, Wolchok JD, Shukla SA, Wu CJ, Peggs KS, Chan TA, Hadrup SR, Quezada SA, Swanton C (2016) Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351(6280):1463–1469. https://doi.org/10.1126/science.aaf1490

    CAS  Article  PubMed  Google Scholar 

  21. Creighton CJ (2012) The molecular profile of luminal B breast cancer. Biologics 6:289–297. https://doi.org/10.2147/BTT.S29923

    CAS  Article  PubMed  Google Scholar 

  22. Budczies J, Bockmayr M, Denkert C, Klauschen F, Lennerz JK, Gyorffy B, Dietel M, Loibl S, Weichert W, Stenzinger A (2015) Classical pathology and mutational load of breast cancer—integration of two worlds. J Pathol Clin Res 1(4):225–238. https://doi.org/10.1002/cjp2.25

    CAS  Article  PubMed  Google Scholar 

  23. Munn DH, Bronte V (2016) Immune suppressive mechanisms in the tumor microenvironment. Curr Opin Immunol 39:1–6. https://doi.org/10.1016/j.coi.2015.10.009

    CAS  Article  PubMed  Google Scholar 

  24. Rothenberger NJ, Somasundaram A, Stabile LP (2018) The Role of the Estrogen Pathway in the Tumor Microenvironment. Int J Mol Sci 19 (2). https://doi.org/10.3390/ijms19020611

    Article  Google Scholar 

  25. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, Mc Henry KT, Pinchback RM, Ligon AH, Cho YJ, Haery L, Greulich H, Reich M, Winckler W, Lawrence MS, Weir BA, Tanaka KE, Chiang DY, Bass AJ, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S, Maher E, Kaye FJ, Sasaki H, Tepper JE, Fletcher JA, Tabernero J, Baselga J, Tsao MS, Demichelis F, Rubin MA, Janne PA, Daly MJ, Nucera C, Levine RL, Ebert BL, Gabriel S, Rustgi AK, Antonescu CR, Ladanyi M, Letai A, Garraway LA, Loda M, Beer DG, True LD, Okamoto A, Pomeroy SL, Singer S, Golub TR, Lander ES, Getz G, Sellers WR, Meyerson M (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463(7283):899–905. https://doi.org/10.1038/nature08822

    CAS  Article  PubMed  Google Scholar 

  26. Teh JLF, Aplin AE (2018) Arrested Developments: CDK4/6 Inhibitor Resistance and Alterations in the Tumor Immune Microenvironment. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-18-1967

    Article  PubMed  Google Scholar 

  27. Whiteside TL (2014) Induced regulatory T cells in inhibitory microenvironments created by cancer. Expert Opin Biol Ther 14(10):1411–1425. https://doi.org/10.1517/14712598.2014.927432

    CAS  Article  PubMed  Google Scholar 

  28. deLeeuw RJ, Kost SE, Kakal JA, Nelson BH (2012) The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin Cancer Res 18(11):3022–3029. https://doi.org/10.1158/1078-0432.CCR-11-3216

    CAS  Article  PubMed  Google Scholar 

  29. Ruffell B, Coussens LM (2015) Macrophages and therapeutic resistance in cancer. Cancer Cell 27(4):462–472. https://doi.org/10.1016/j.ccell.2015.02.015

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Santoni M, Massari F, Amantini C, Nabissi M, Maines F, Burattini L, Berardi R, Santoni G, Montironi R, Tortora G, Cascinu S (2013) Emerging role of tumor-associated macrophages as therapeutic targets in patients with metastatic renal cell carcinoma. Cancer Immunol Immunother 62(12):1757–1768. https://doi.org/10.1007/s00262-013-1487-6

    CAS  Article  PubMed  Google Scholar 

  31. Hoskoppal D, Reisenbichler ES (2018) Can tumor-associated macrophages in ductal carcinoma in situ (DCIS) on biopsy predict invasive carcinoma on excision? Hum Pathol. https://doi.org/10.1016/j.humpath.2018.07.023

    Article  PubMed  Google Scholar 

  32. Fortis SP, Sofopoulos M, Sotiriadou NN, Haritos C, Vaxevanis CK, Anastasopoulou EA, Janssen N, Arnogiannaki N, Ardavanis A, Pawelec G, Perez SA, Baxevanis CN (2017) Differential intratumoral distributions of CD8 and CD163 immune cells as prognostic biomarkers in breast cancer. J Immunother Cancer 5:39. https://doi.org/10.1186/s40425-017-0240-7

    Article  PubMed  PubMed Central  Google Scholar 

  33. Wu SQ, Xu R, Li XF, Zhao XK, Qian BZ (2018) Prognostic roles of tumor associated macrophages in bladder cancer: a system review and meta-analysis. Oncotarget 9(38):25294–25303. https://doi.org/10.18632/oncotarget.25334

    Article  PubMed  PubMed Central  Google Scholar 

  34. Pfitzner BM, Lederer B, Lindner J, Solbach C, Engels K, Rezai M, Dohnal K, Tesch H, Hansmann ML, Salat C, Beer M, Schneeweiss A, Sinn P, Bankfalvi A, Darb-Esfahani S, von Minckwitz G, Sinn BV, Kronenwett R, Weber K, Denkert C, Loibl S (2018) Clinical relevance and concordance of HER2 status in local and central testing-an analysis of 1581 HER2-positive breast carcinomas over 12 years. Mod Pathol 31(4):607–615. https://doi.org/10.1038/modpathol.2017.171

    CAS  Article  PubMed  Google Scholar 

  35. Denkert C, Wienert S, Poterie A, Loibl S, Budczies J, Badve S, Bago-Horvath Z, Bane A, Bedri S, Brock J, Chmielik E, Christgen M, Colpaert C, Demaria S, Van den Eynden G, Floris G, Fox SB, Gao D, Ingold Heppner B, Kim SR, Kos Z, Kreipe HH, Lakhani SR, Penault-Llorca F, Pruneri G, Radosevic-Robin N, Rimm DL, Schnitt SJ, Sinn BV, Sinn P, Sirtaine N, O’Toole SA, Viale G, Van de Vijver K, de Wind R, von Minckwitz G, Klauschen F, Untch M, Fasching PA, Reimer T, Willard-Gallo K, Michiels S, Loi S, Salgado R (2016) Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: results of the ring studies of the international immuno-oncology biomarker working group. Mod Pathol 29(10):1155–1164. https://doi.org/10.1038/modpathol.2016.109

    CAS  Article  PubMed  Google Scholar 

  36. Zheng H, Zeltsman M, Zauderer MG, Eguchi T, Vaghjiani RG, Adusumilli PS (2017) Chemotherapy-induced immunomodulation in non-small-cell lung cancer: a rationale for combination chemoimmunotherapy. Immunotherapy 9(11):913–927. https://doi.org/10.2217/imt-2017-0052

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G (2008) Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8(1):59–73. https://doi.org/10.1038/nri2216

    CAS  Article  PubMed  Google Scholar 

  38. Liljenfeldt L, Gkirtzimanaki K, Vyrla D, Svensson E, Loskog AS, Eliopoulos AG (2014) Enhanced therapeutic anti-tumor immunity induced by co-administration of 5-fluorouracil and adenovirus expressing CD40 ligand. Cancer Immunol Immunother 63(3):273–282. https://doi.org/10.1007/s00262-013-1507-6

    CAS  Article  PubMed  Google Scholar 

  39. Fritzell S, Sanden E, Eberstal S, Visse E, Darabi A, Siesjo P (2013) Intratumoral temozolomide synergizes with immunotherapy in a T cell-dependent fashion. Cancer Immunol Immunother 62(9):1463–1474. https://doi.org/10.1007/s00262-013-1449-z

    CAS  Article  PubMed  Google Scholar 

  40. Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von Torne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28(1):105–113. https://doi.org/10.1200/JCO.2009.23.7370

    CAS  Article  Google Scholar 

  41. Vacchelli E, Enot DP, Pietrocola F, Zitvogel L, Kroemer G (2016) Impact of pattern recognition receptors on the prognosis of breast cancer patients undergoing adjuvant chemotherapy. Cancer Res 76(11):3122–3126. https://doi.org/10.1158/0008-5472.CAN-16-0294

    CAS  Article  PubMed  Google Scholar 

  42. Menard C, Martin F, Apetoh L, Bouyer F, Ghiringhelli F (2008) Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity. Cancer Immunol Immunother 57(11):1579–1587. https://doi.org/10.1007/s00262-008-0505-6

    CAS  Article  PubMed  Google Scholar 

  43. Nawaz S, Heindl A, Koelble K, Yuan Y (2015) Beyond immune density: critical role of spatial heterogeneity in estrogen receptor-negative breast cancer. Mod Pathol 28(12):1621. https://doi.org/10.1038/modpathol.2015.133

    Article  PubMed  Google Scholar 

  44. Dushyanthen S, Beavis PA, Savas P, Teo ZL, Zhou C, Mansour M, Darcy PK, Loi S (2015) Relevance of tumor-infiltrating lymphocytes in breast cancer. BMC Med 13:202. https://doi.org/10.1186/s12916-015-0431-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Wein L, Savas P, Luen SJ, Virassamy B, Salgado R, Loi S (2017) Clinical validity and utility of tumor-infiltrating lymphocytes in routine clinical practice for breast cancer patients: current and future directions. Front Oncol 7:156. https://doi.org/10.3389/fonc.2017.00156

    Article  PubMed  PubMed Central  Google Scholar 

  46. McIntire PJ, Irshaid L, Liu Y, Chen Z, Menken F, Nowak E, Shin SJ, Ginter PS (2018) Hot spot and whole-tumor enumeration of CD8(+) tumor-infiltrating lymphocytes utilizing digital image analysis is prognostic in triple-negative breast cancer. Clin Breast Cancer. https://doi.org/10.1016/j.clbc.2018.04.019

    Article  PubMed  Google Scholar 

  47. Miyan M, Schmidt-Mende J, Kiessling R, Poschke I, de Boniface J (2016) Differential tumor infiltration by T-cells characterizes intrinsic molecular subtypes in breast cancer. J Transl Med 14(1):227. https://doi.org/10.1186/s12967-016-0983-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Galon J, Angell HK, Bedognetti D, Marincola FM (2013) The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 39(1):11–26. https://doi.org/10.1016/j.immuni.2013.07.008

    CAS  Article  PubMed  Google Scholar 

  49. Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, Sucker A, Hillen U, Foppen MHG, Goldinger SM, Utikal J, Hassel JC, Weide B, Kaehler KC, Loquai C, Mohr P, Gutzmer R, Dummer R, Gabriel S, Wu CJ, Schadendorf D, Garraway LA (2015) Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350(6257):207–211. https://doi.org/10.1126/science.aad0095

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Popovic A, Jaffee EM, Zaidi N (2018) Emerging strategies for combination checkpoint modulators in cancer immunotherapy. J Clin Invest 128(8):3209–3218. https://doi.org/10.1172/JCI120775

    Article  PubMed  PubMed Central  Google Scholar 

  51. Gajewski TF, Corrales L, Williams J, Horton B, Sivan A, Spranger S (2017) Cancer immunotherapy targets based on understanding the T cell-inflamed versus non-T cell-inflamed tumor microenvironment. Adv Exp Med Biol 1036:19–31. https://doi.org/10.1007/978-3-319-67577-0_2

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Mlecnik B, Bindea G, Angell HK, Maby P, Angelova M, Tougeron D, Church SE, Lafontaine L, Fischer M, Fredriksen T, Sasso M, Bilocq AM, Kirilovsky A, Obenauf AC, Hamieh M, Berger A, Bruneval P, Tuech JJ, Sabourin JC, Le Pessot F, Mauillon J, Rafii A, Laurent-Puig P, Speicher MR, Trajanoski Z, Michel P, Sesboue R, Frebourg T, Pages F, Valge-Archer V, Latouche JB, Galon J (2016) Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity 44(3):698–711. https://doi.org/10.1016/j.immuni.2016.02.025

    CAS  Article  PubMed  Google Scholar 

  53. Tokalov SV, Abolmaali ND (2010) Protection of p53 wild type cells from taxol by nutlin-3 in the combined lung cancer treatment. BMC Cancer 10:57. https://doi.org/10.1186/1471-2407-10-57

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Middel P, Brauneck S, Meyer W, Radzun HJ (2010) Chemokine-mediated distribution of dendritic cell subsets in renal cell carcinoma. BMC Cancer 10:578. https://doi.org/10.1186/1471-2407-10-578

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Moussion C, Girard JP (2011) Dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules. Nature 479(7374):542–546. https://doi.org/10.1038/nature10540

    CAS  Article  PubMed  Google Scholar 

  56. Martinet L, Garrido I, Filleron T, Le Guellec S, Bellard E, Fournie JJ, Rochaix P, Girard JP (2011) Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res 71(17):5678–5687. https://doi.org/10.1158/0008-5472.CAN-11-0431

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Mlecnik B, Bindea G, Kirilovsky A, Angell HK, Obenauf AC, Tosolini M, Church SE, Maby P, Vasaturo A, Angelova M, Fredriksen T, Mauger S, Waldner M, Berger A, Speicher MR, Pages F, Valge-Archer V, Galon J (2016) The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis. Sci Transl Med 8(327):327ra326. https://doi.org/10.1126/scitranslmed.aad6352

    CAS  Article  Google Scholar 

  58. Pages F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Marliot F, Bruneval P, Zatloukal K, Trajanoski Z, Berger A, Fridman WH, Galon J (2009) In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 27(35):5944–5951. https://doi.org/10.1200/JCO.2008.19.6147

    CAS  Article  PubMed  Google Scholar 

  59. Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G, Meatchi T, Bruneval P, Trajanoski Z, Fridman WH, Pages F, Galon J (2011) Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 29(6):610–618. https://doi.org/10.1200/JCO.2010.30.5425

    Article  PubMed  PubMed Central  Google Scholar 

  60. Denkert C, von Minckwitz G, Brase JC, Sinn BV, Gade S, Kronenwett R, Pfitzner BM, Salat C, Loi S, Schmitt WD, Schem C, Fisch K, Darb-Esfahani S, Mehta K, Sotiriou C, Wienert S, Klare P, Andre F, Klauschen F, Blohmer JU, Krappmann K, Schmidt M, Tesch H, Kummel S, Sinn P, Jackisch C, Dietel M, Reimer T, Untch M, Loibl S (2015) 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 33(9):983–991. https://doi.org/10.1200/JCO.2014.58.1967

    CAS  Article  PubMed  Google Scholar 

  61. Miao D, Margolis CA, Vokes NI, Liu D, Taylor-Weiner A, Wankowicz SM, Adeegbe D, Keliher D, Schilling B, Tracy A, Manos M, Chau NG, Hanna GJ, Polak P, Rodig SJ, Signoretti S, Sholl LM, Engelman JA, Getz G, Janne PA, Haddad RI, Choueiri TK, Barbie DA, Haq R, Awad MM, Schadendorf D, Hodi FS, Bellmunt J, Wong KK, Hammerman P, Van Allen EM (2018) Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors. Nat Genet 50(9):1271–1281. https://doi.org/10.1038/s41588-018-0200-2

    CAS  Article  PubMed  Google Scholar 

  62. Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R (2017) Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res 23(15):4242–4250. https://doi.org/10.1158/1078-0432.CCR-16-3133

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. Miao D, Margolis CA, Gao W, Voss MH, Li W, Martini DJ, Norton C, Bosse D, Wankowicz SM, Cullen D, Horak C, Wind-Rotolo M, Tracy A, Giannakis M, Hodi FS, Drake CG, Ball MW, Allaf ME, Snyder A, Hellmann MD, Ho T, Motzer RJ, Signoretti S, Kaelin WG Jr, Choueiri TK, Van Allen EM (2018) Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359(6377):801–806. https://doi.org/10.1126/science.aan5951

    CAS  Article  PubMed  Google Scholar 

  64. Galon J, Bruni D (2019) Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov 18(3):197–218. https://doi.org/10.1038/s41573-018-0007-y

    CAS  Article  PubMed  Google Scholar 

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  1. Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Ave., 115 22, Athens, Greece

    Constantin N. Baxevanis, Sotirios P. Fortis & Sonia A. Perez

  2. Pathology Department, Saint Savas Cancer Hospital, Athens, Greece

    Michael Sofopoulos

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Constantin N. Baxevanis conceived the manuscript. All authors wrote and edited the manuscript and approved its final version.

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Baxevanis, C.N., Sofopoulos, M., Fortis, S.P. et al. The role of immune infiltrates as prognostic biomarkers in patients with breast cancer. Cancer Immunol Immunother 68, 1671–1680 (2019). https://doi.org/10.1007/s00262-019-02327-7

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  • DOI: https://doi.org/10.1007/s00262-019-02327-7

Keywords

  • Breast cancer
  • TILs
  • CD163+ cells
  • CD8+ T cells
  • Biomarkers
  • TIMO XIV