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Natural and therapy-induced immunosurveillance in breast cancer

Nature Medicine volume 21, pages 1128–1138 (2015)Cite this article

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Abstract

The immunosurveillance theory postulates that tumors evolve and progress in an uncontrolled fashion only when anticancer immune responses fail. Natural immunosurveillance clearly influences human breast cancer (BC) progression because the prognosis of BC patients is dictated by the density, composition and activity of the tumor immune infiltrate at diagnosis. Moreover, chemotherapeutic and radiotherapeutic regimens commonly employed for the treatment of BC affect the tumor immune infiltrate, and accumulating data suggest that the clinical efficacy of these treatments is largely determined by T cell–dependent tumor-specific immune responses. In addition, the mechanism of action of targeted anticancer therapeutics, such as the erb-b2 receptor tyrosine kinase 2 (ERBB2)-targeting agent trastuzumab, involves the innate and adaptive arms of the immune system. In this Review, we discuss these findings as well as preliminary evidence indicating that immunotherapy constitutes a promising option for the treatment of BC. Moreover, we point out that the successful implementation of immunotherapy to BC management requires the optimization of current immunotherapeutic regimens and the identification of immunological biomarkers that enable improved risk stratification and the design of personalized, dynamic treatment plans.

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Figure 1: Cancer cell-intrinsic and -extrinsic factors influencing the immune infiltrate of breast cancers.
Figure 2: Immunogenic cell death.
Figure 3: ERBB2 as a target in breast cancer therapy.
Figure 4: Immunotherapeutic regimens against BC that have been investigated in preclinical settings and/or are currently being evaluated in clinical trials.

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References

  1. Hanahan, D. & Weinberg, R.A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Hanahan, D. & Weinberg, R.A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Schreiber, R.D., Old, L.J. & Smyth, M.J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Shankaran, V. et al. IFN-γ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Zitvogel, L., Tesniere, A. & Kroemer, G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat. Rev. Immunol. 6, 715–727 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Page, D.B., Postow, M.A., Callahan, M.K., Allison, J.P. & Wolchok, J.D. Immune modulation in cancer with antibodies. Annu. Rev. Med. 65, 185–202 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Postow, M.A., Callahan, M.K. & Wolchok, J.D. Immune checkpoint blockade in cancer therapy. J. Clin. Oncol. 33, 1974–1982 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zitvogel, L., Galluzzi, L., Smyth, M.J. & Kroemer, G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39, 74–88 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Gubin, M.M. et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577–581 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Massink, M.P. et al. Proper genomic profiling of (BRCA1-mutated) basal-like breast carcinomas requires prior removal of tumor infiltrating lymphocytes. Mol. Oncol. 9, 877–888 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Perou, C.M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Staaf, J. et al. Identification of subtypes in human epidermal growth factor receptor 2–positive breast cancer reveals a gene signature prognostic of outcome. J. Clin. Oncol. 28, 1813–1820 (2010).

    Article  PubMed  Google Scholar 

  13. Lehmann, B.D. et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J. Clin. Invest. 121, 2750–2767 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Finak, G. et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat. Med. 14, 518–527 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Sistigu, A. et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat. Med. 20, 1301–1309 (2014).

    Article  CAS  PubMed  Google Scholar 

  16. Stoll, G. et al. Immune-related gene signatures predict the outcome of neoadjuvant chemotherapy. OncoImmunology 3, e27884 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Denkert, 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. 33, 983–991 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Rastogi, P. et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J. Clin. Oncol. 26, 778–785 (2008).

    Article  PubMed  Google Scholar 

  19. Stoll, G. et al. Meta-analysis of organ-specific differences in the structure of the immune infiltrate in major malignancies. Oncotarget 6, 11894–11909 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Liu, S. et al. Prognostic significance of FOXP3+ tumor-infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration. Breast Cancer Res. 16, 432 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Miyashita, M. et al. 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, 525–534 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Denkert, C. et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J. Clin. Oncol. 28, 105–113 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Salgado, R. et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann. Oncol. 26, 259–271 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Adams, S. et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J. Clin. Oncol. 32, 2959–2966 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Loi, S. 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. 31, 860–867 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Mao, 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 9, e115103 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dieci, M.V. et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials. Ann. Oncol. 26, 1698–1704 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nawaz, S., Heindl, A., Koelble, K. & Yuan, Y. Beyond immune density: critical role of spatial heterogeneity in estrogen receptor-negative breast cancer. Mod. Pathol. 28, 766–777 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Martinet, L. et al. Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res. 71, 5678–5687 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Hornychová, H. et al. Tumor-infiltrating lymphocytes predict response to neoadjuvant chemotherapy in patients with breast carcinoma. Cancer Invest. 26, 1024–1031 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Ali, H.R. et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann. Oncol. 25, 1536–1543 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Brown, J.R. et al. Multiplexed quantitative analysis of CD3, CD8, and CD20 predicts response to neoadjuvant chemotherapy in breast cancer. Clin. Cancer Res. 20, 5995–6005 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gu-Trantien, C. et al. CD4+ follicular helper T cell infiltration predicts breast cancer survival. J. Clin. Invest. 123, 2873–2892 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dieu-Nosjean, M.C. et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J. Clin. Oncol. 26, 4410–4417 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Fridman, W.H., Pages, F., Sautes-Fridman, C. & Galon, J. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer 12, 298–306 (2012).

    Article  CAS  PubMed  Google Scholar 

  36. Mimura, K. et al. T cell recognition of HLA-A2 restricted tumor antigens is impaired by the oncogene HER2. Int. J. Cancer 128, 390–401 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Inoue, M. et al. Expression of MHC Class I on breast cancer cells correlates inversely with HER2 expression. OncoImmunol. 1, 1104–1110 (2012).

    Article  Google Scholar 

  38. Kaneko, K. et al. Clinical implication of HLA class I expression in breast cancer. BMC Cancer 11, 454 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. de Kruijf, E.M. et al. The predictive value of HLA class I tumor cell expression and presence of intratumoral Tregs for chemotherapy in patients with early breast cancer. Clin. Cancer Res. 16, 1272–1280 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Madjd, Z., Spendlove, I., Pinder, S.E., Ellis, I.O. & Durrant, L.G. Total loss of MHC class I is an independent indicator of good prognosis in breast cancer. Int. J. Cancer 117, 248–255 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Neefjes, J., Jongsma, M.L., Paul, P. & Bakke, O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat. Rev. Immunol. 11, 823–836 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Richardsen, E., Uglehus, R.D., Johnsen, S.H. & Busund, L.T. Macrophage-colony stimulating factor (CSF1) predicts breast cancer progression and mortality. Anticancer Res. 35, 865–874 (2015).

    PubMed  Google Scholar 

  43. DeNardo, D.G. et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Senovilla, L., Aranda, F., Galluzzi, L. & Kroemer, G. Impact of myeloid cells on the efficacy of anticancer chemotherapy. Curr. Opin. Immunol. 30, 24–31 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Tiainen, S. et al. High numbers of macrophages, especially M2-like (CD163-positive), correlate with hyaluronan accumulation and poor outcome in breast cancer. Histopathol. 66, 873–883 (2015).

    Article  Google Scholar 

  46. Drews-Elger, K. et al. Infiltrating S100A8+ myeloid cells promote metastatic spread of human breast cancer and predict poor clinical outcome. Breast Cancer Res. Treat. 148, 41–59 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Iqbal, J., Ginsburg, O., Rochon, P.A., Sun, P. & Narod, S.A. Differences in breast cancer stage at diagnosis and cancer-specific survival by race and ethnicity in the United States. J. Am. Med. Assoc. 313, 165–173 (2015).

    Article  CAS  Google Scholar 

  48. Zitvogel, L. et al. Cancer and the gut microbiota: an unexpected link. Sci. Transl. Med. 7, 271ps271 (2015).

    Article  CAS  Google Scholar 

  49. Rossini, A. et al. Influence of antibiotic treatment on breast carcinoma development in proto-neu transgenic mice. Cancer Res. 66, 6219–6224 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Kassayová, M. et al. Preventive effects of probiotic bacteria Lactobacillus plantarum and dietary fiber in chemically-induced mammary carcinogenesis. Anticancer Res. 34, 4969–4975 (2014).

    PubMed  Google Scholar 

  51. Velicer, C.M. et al. Antibiotic use in relation to the risk of breast cancer. J. Am. Med. Assoc. 291, 827–835 (2004).

    Article  CAS  Google Scholar 

  52. Rutkowski, M.R. et al. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell 27, 27–40 (2015).

    Article  CAS  PubMed  Google Scholar 

  53. Howe, L.R., Subbaramaiah, K., Hudis, C.A. & Dannenberg, A.J. Molecular pathways: adipose inflammation as a mediator of obesity-associated cancer. Clin. Cancer Res. 19, 6074–6083 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Azim, H.A. Jr. et al. Tumour infiltrating lymphocytes (TILs) in breast cancer during pregnancy. Breast 24, 290–293 (2015).

    Article  PubMed  Google Scholar 

  55. Martinson, H.A., Jindal, S., Durand-Rougely, C., Borges, V.F. & Schedin, P. Wound healing-like immune program facilitates postpartum mammary gland involution and tumor progression. Int. J. Cancer 136, 1803–1813 (2015).

    Article  CAS  PubMed  Google Scholar 

  56. Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat. Med. 15, 1170–1178 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Ma, Y. et al. Contribution of IL-17-producing gamma delta T cells to the efficacy of anticancer chemotherapy. J. Exp. Med. 208, 491–503 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Senovilla, L. et al. An immunosurveillance mechanism controls cancer cell ploidy. Science 337, 1678–1684 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Shiao, S.L. et al. TH2-polarized CD4+ T cells and macrophages limit efficacy of radiotherapy. Cancer Immunol. Res. 3, 518–525 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mattarollo, S.R. et al. Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors. Cancer Res. 71, 4809–4820 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Apetoh, L. et al. Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050–1059 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Hossain, D.M. et al. FoxP3 acts as a cotranscription factor with STAT3 in tumor-induced regulatory T cells. Immunity 39, 1057–1069 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Ma, Y. et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38, 729–741 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Klug, F. et al. Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24, 589–602 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Wumkes, M.L. et al. Serum antibody response to influenza virus vaccination during chemotherapy treatment in adult patients with solid tumours. Vaccine 31, 6177–6184 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Péguillet, I. et al. High numbers of differentiated effector CD4 T cells are found in patients with cancer and correlate with clinical response after neoadjuvant therapy of breast cancer. Cancer Res. 74, 2204–2216 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Demaria, S. et al. Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin. Cancer Res. 7, 3025–3030 (2001).

    CAS  PubMed  Google Scholar 

  71. Ruffell, B. et al. Leukocyte composition of human breast cancer. Proc. Natl. Acad. Sci. USA 109, 2796–2801 (2012).

    Article  PubMed  Google Scholar 

  72. Dieci, M.V. et al. Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann. Oncol. 25, 611–618 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ladoire, S. 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. 14, 2413–2420 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Bidwell, B.N. et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat. Med. 18, 1224–1231 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. Chao, M.P., Majeti, R. & Weissman, I.L. Programmed cell removal: a new obstacle in the road to developing cancer. Nat. Rev. Cancer 12, 58–67 (2012).

    Article  CAS  Google Scholar 

  76. Baccelli, I. et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat. Biotechnol. 31, 539–544 (2013).

    Article  CAS  PubMed  Google Scholar 

  77. Baccelli, I. et al. Co-expression of MET and CD47 is a novel prognosticator for survival of luminal breast cancer patients. Oncotarget 5, 8147–8160 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Galluzzi, L. et al. Autophagy in malignant transformation and cancer progression. EMBO J. 34, 856–880 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. He, Y. et al. The prognostic value of autophagy-related markers beclin-1 and microtubule-associated protein light chain 3B in cancers: a systematic review and meta-analysis. Tumour Biol. 35, 7317–7326 (2014).

    Article  CAS  PubMed  Google Scholar 

  81. Tang, H. et al. Decreased mRNA expression in human breast cancer is associated with estrogen receptor-negative subtypes and poor prognosis. EBioMedicine 2, 255–263 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Ladoire, S. et al. LC3B puncta and HMGB1 expression predict residual risk of relapse after adjuvant chemotherapy in breast cancer. Autophagy (in the press).

  83. Loi, S. et al. CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc. Natl. Acad. Sci. USA 110, 11091–11096 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Arnold, T. et al. Plasma HMGB-1 after the initial dose of epirubicin/docetaxel in cancer. Eur. J. Clin. Invest. 43, 286–291 (2013).

    Article  CAS  PubMed  Google Scholar 

  85. Yamazaki, T. et al. Defective immunogenic cell death of HMGB1-deficient tumors: compensatory therapy with TLR4 agonists. Cell Death Differ. 21, 69–78 (2014).

    Article  CAS  PubMed  Google Scholar 

  86. Khallouf, H. et al. 5-Fluorouracil and interferon-alpha immunochemotherapy enhances immunogenicity of murine pancreatic cancer through upregulation of NKG2D ligands and MHC class I. J. Immunother. 35, 245–253 (2012).

    Article  CAS  PubMed  Google Scholar 

  87. Dimeloe, S. et al. Human regulatory T cells lack the cyclophosphamide-extruding transporter ABCB1 and are more susceptible to cyclophosphamide-induced apoptosis. Eur. J. Immunol. 44, 3614–3620 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. Vincent, J. et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 70, 3052–3061 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. Liechtenstein, T. et al. A highly efficient tumor-infiltrating MDSC differentiation system for discovery of anti-neoplastic targets, which circumvents the need for tumor establishment in mice. Oncotarget 5, 7843–7857 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Rimawi, M.F., Schiff, R. & Osborne, C.K. Targeting HER2 for the treatment of breast cancer. Annu. Rev. Med. 66, 111–128 (2015).

    Article  CAS  PubMed  Google Scholar 

  91. Gennari, R. et al. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin. Cancer Res. 10, 5650–5655 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Clynes, R.A., Towers, T.L., Presta, L.G. & Ravetch, J.V. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat. Med. 6, 443–446 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Musolino, A. et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J. Clin. Oncol. 26, 1789–1796 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Norton, N. et al. Association studies of Fcγ receptor polymorphisms with outcome in HER2+ breast cancer patients treated with trastuzumab in NCCTG (Alliance) Trial N9831. Cancer Immunol. Res. 2, 962–969 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Tamura, K. et al. FcγR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer. Ann. Oncol. 22, 1302–1307 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Hurvitz, S.A. et al. Analysis of Fcγ receptor IIIa and IIa polymorphisms: lack of correlation with outcome in trastuzumab-treated breast cancer patients. Clin. Cancer Res. 18, 3478–3486 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Loi, S. 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. 25, 1544–1550 (2014).

    Article  CAS  PubMed  Google Scholar 

  98. Savas, P., Caramia, F., Teo, Z.L. & Loi, S. Oncogene addiction and immunity: clinical implications of tumour infiltrating lymphocytes in breast cancers overexpressing the HER2/neu oncogene. Curr. Opin. Oncol. 26, 562–567 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Perez, E.A. 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. 33, 701–708 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Suzuki, E. et al. Trogocytosis-mediated expression of HER2 on immune cells may be associated with a pathological complete response to trastuzumab-based primary systemic therapy in HER2-overexpressing breast cancer patients. BMC Cancer 15, 39 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Beano, A. et al. Correlation between NK function and response to trastuzumab in metastatic breast cancer patients. J. Transl. Med. 6, 25 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kohrt, H.E. et al. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J. Clin. Invest. 122, 1066–1075 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Park, S. et al. The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell 18, 160–170 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Stagg, J. et al. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc. Natl. Acad. Sci. USA 108, 7142–7147 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Gil, E.Y. et al. Vaccination with ErbB-2 peptides prevents cancer stem cell expansion and suppresses the development of spontaneous tumors in MMTV-PyMT transgenic mice. Breast Cancer Res. Treat. 147, 69–80 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Mittendorf, E.A. et al. Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients. Ann. Oncol. 25, 1735–1742 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Clive, K.S. et al. The GP2 peptide: a HER2/neu-based breast cancer vaccine. J. Surg. Oncol. 105, 452–458 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Ernst, B. & Anderson, K.S. Immunotherapy for the treatment of breast cancer. Curr. Oncol. Rep. 17, 5 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. Melero, I. et al. Therapeutic vaccines for cancer: an overview of clinical trials. Nat. Rev. Clin. Oncol. 11, 509–524 (2014).

    Article  CAS  PubMed  Google Scholar 

  110. Wang, S. et al. Therapeutic targeting of erbB3 with MM-121/SAR256212 enhances antitumor activity of paclitaxel against erbB2-overexpressing breast cancer. Breast Cancer Res. 15, R101 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Huang, J. et al. The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells. Mol. Cancer 12, 134 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Vacchelli, E. et al. Trial watch: Tumor-targeting monoclonal antibodies for oncological indications. OncoImmunol. 4, e985940 (2015).

    Article  CAS  Google Scholar 

  113. Miller, M.J., Foy, K.C., Overholser, J.P., Nahta, R. & Kaumaya, P.T. HER-3 peptide vaccines/mimics: combined therapy with IGF-1R, HER-2, and HER-1 peptides induces synergistic antitumor effects against breast and pancreatic cancer cells. OncoImmunology 3, e956012 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Galluzzi, L. et al. Classification of current anticancer immunotherapies. Oncotarget 5, 12472–12508 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Wang, Z.X. et al. Adoptive cellular immunotherapy for the treatment of patients with breast cancer: a meta-analysis. Cytotherapy 16, 934–945 (2014).

    Article  CAS  PubMed  Google Scholar 

  116. Pan, K. et al. Clinical activity of adjuvant cytokine-induced killer cell immunotherapy in patients with post-mastectomy triple-negative breast cancer. Clin. Cancer Res. 20, 3003–3011 (2014).

    Article  CAS  PubMed  Google Scholar 

  117. Lum, L.G. et al. Targeted T-cell therapy in stage IV breast cancer: A phase I clinical trial. Clin. Cancer Res. 21, 2305–2314 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Weidle, U.H., Kontermann, R.E. & Brinkmann, U. Tumor-antigen-binding bispecific antibodies for cancer treatment. Semin. Oncol. 41, 653–660 (2014).

    Article  CAS  PubMed  Google Scholar 

  119. Nanda, R. et al. Abstract Si-09: a phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer (in Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9–13; San Antonio, Texas). Cancer Res. 75, S1–09 (2014).

    Google Scholar 

  120. Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. Postow, M.A. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Schalper, K.A. et al. In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin. Cancer Res. 20, 2773–2782 (2014).

    Article  CAS  PubMed  Google Scholar 

  123. Sabatier, R. et al. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget 6, 5449–5464 (2015).

    Article  PubMed  Google Scholar 

  124. Sun, S. et al. PD-1(+) immune cell infiltration inversely correlates with survival of operable breast cancer patients. Cancer Immunol. Immunother. 63, 395–406 (2014).

    Article  CAS  PubMed  Google Scholar 

  125. Wimberly, H. et al. PD-L1 expression correlates with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy in breast cancer. Cancer Immunol. Res. 3, 326–332 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Muenst, S. et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res. Treat. 146, 15–24 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Le, D.T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Karyampudi, L. et al. Accumulation of memory precursor CD8 T cells in regressing tumors following combination therapy with vaccine and anti-PD-1 antibody. Cancer Res. 74, 2974–2985 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Allard, B., Pommey, S., Smyth, M.J. & Stagg, J. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin. Cancer Res. 19, 5626–5635 (2013).

    Article  CAS  PubMed  Google Scholar 

  130. Mittal, D. et al. Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res. 74, 3652–3658 (2014).

    Article  CAS  PubMed  Google Scholar 

  131. Coussens, L.M., Zitvogel, L. & Palucka, A.K. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 339, 286–291 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Gillgrass, A., Gill, N., Babian, A. & Ashkar, A.A. The absence or overexpression of IL-15 drastically alters breast cancer metastasis via effects on NK cells, CD4 T cells, and macrophages. J. Immunol. 193, 6184–6191 (2014).

    Article  CAS  PubMed  Google Scholar 

  133. Linnemann, C. et al. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat. Med. 21, 81–85 (2015).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France

    Guido Kroemer, Laura Senovilla & Lorenzo Galluzzi

  2. INSERM, Paris, U1138, France

    Guido Kroemer, Laura Senovilla & Lorenzo Galluzzi

  3. Université Paris Descartes/Paris V, Sorbonne, Paris, France

    Guido Kroemer, Laura Senovilla & Lorenzo Galluzzi

  4. Université Pierre et Marie Curie/Paris VI, Paris, France

    Guido Kroemer, Laura Senovilla & Lorenzo Galluzzi

  5. Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France

    Guido Kroemer

  6. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Guido Kroemer

  7. Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden

    Guido Kroemer

  8. Gustave Roussy Comprehensive Cancer Institute, Villejuif, France

    Laura Senovilla, Lorenzo Galluzzi, Fabrice André & Laurence Zitvogel

  9. University of Paris Sud/Paris XI, Le Kremlin-Bicêtre, France

    Fabrice André & Laurence Zitvogel

  10. INSERM, Villejuif, U1015, France

    Laurence Zitvogel

  11. Center of Clinical Investigations in Biotherapies of Cancer 507 (CICBT 507), Villejuif, France

    Laurence Zitvogel

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  1. Guido Kroemer
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  2. Laura Senovilla
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Correspondence to Guido Kroemer.

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Kroemer, G., Senovilla, L., Galluzzi, L. et al. Natural and therapy-induced immunosurveillance in breast cancer. Nat Med 21, 1128–1138 (2015). https://doi.org/10.1038/nm.3944

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