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Immune Checkpoint Blockade in Breast Cancer Therapy

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  • First Online:
Translational Research in Breast Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1026))

Abstract

Cancer immunotherapy is emerging as the most promising novel strategy for cancer treatment. Cancer immunotherapy is broadly categorized into three forms: immune checkpoint modulation, adoptive cell transfer, and cancer vaccine. Immune checkpoint blockade is demonstrated as the most clinically effective treatment with low immune-related adverse events (irAE). Blockade of PD-1/PD-L1 and CTLA-4 has achieved remarkable success in treating various types of tumors, which sparks great interests in this therapeutic strategy and expands the role of immune checkpoint blockade in treating tumors including breast cancer. Based on the notable results obtained from clinical trials, the United States’ Food and Drug Administration (FDA) has approved multiple CTLA-4 monoclonal antibodies as well as the PD-1/PD-L1 monoclonal antibodies for treatment of different types of tumors. The theories of immunoediting, T-cell exhaustions, and co-stimulatory/co-inhibitory pathways are immunological foundations for immune checkpoint blockade therapy. Breast cancers such as triple negative breast cancer and HER-2 negative breast cancer respond to immune checkpoint blockade therapy due to their high immunogenicity. PD-1/PD-L1 blockade has just received FDA approval as a standard cancer therapy for solid tumors such as breast cancer. Development of immune checkpoint blockade focuses on two directions: one is to identify proper biomarkers of immune checkpoint blockade in breast cancer, and the other is to combine therapies with PD-1/PD-L1 blockade antibodies to achieve optimal clinical outcomes.

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References

  1. Newman LA (2009) Epidemiology of locally advanced breast cancer. Semin Radiat Oncol 19(4):195–203. doi:10.1016/j.semradonc.2009.05.003

    Article  PubMed  Google Scholar 

  2. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O’Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A (2015) Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 16(8):908–918. doi:10.1016/S1470-2045(15)00083-2

    Article  CAS  PubMed  Google Scholar 

  3. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723. doi:10.1056/NEJMoa1003466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454. doi:10.1056/NEJMoa1200690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Topalian SL, Drake CG, Pardoll DM (2012) Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 24(2):207–212. doi:10.1016/j.coi.2011.12.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR, Investigators K (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833. doi:10.1056/NEJMoa1606774

    Article  CAS  PubMed  Google Scholar 

  7. Krishnamurthy A, Jimeno A (2017) Atezolizumab: a novel PD-L1 inhibitor in cancer therapy with a focus in bladder and non-small cell lung cancers. Drugs Today (Barc) 53(4):217–237. doi:10.1358/dot.2017.53.4.2589163

    Article  CAS  Google Scholar 

  8. Farina MS, Lundgren KT, Bellmunt J (2017) Immunotherapy in urothelial cancer: recent results and future perspectives. Drugs. doi:10.1007/s40265-017-0748-7

  9. Sharma P, Allison JP (2015) Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161(2):205–214. doi:10.1016/j.cell.2015.03.030

    Article  CAS  PubMed  Google Scholar 

  10. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526. doi:10.1056/NEJMoa1104621

    Article  CAS  PubMed  Google Scholar 

  11. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372(4):320–330. doi:10.1056/NEJMoa1412082

    Article  CAS  PubMed  Google Scholar 

  12. June CH (2007) Adoptive T cell therapy for cancer in the clinic. J Clin Invest 117(6):1466–1476. doi:10.1172/JCI32446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. June CH (2007) Principles of adoptive T cell cancer therapy. J Clin Invest 117(5):1204–1212. doi:10.1172/JCI31446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH (2011) T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl med 3 (95):95ra73. doi:10.1126/scitranslmed.3002842

  15. Kershaw MH, Westwood JA, Darcy PK (2013) Gene-engineered T cells for cancer therapy. Nat Rev Cancer 13(8):525–541. doi:10.1038/nrc3565

    Article  CAS  PubMed  Google Scholar 

  16. Hay KA, Turtle CJ (2017) Chimeric antigen receptor (CAR) T cells: lessons learned from targeting of CD19 in B-cell malignancies. Drugs 77(3):237–245. doi:10.1007/s40265-017-0690-8

    Article  CAS  PubMed  Google Scholar 

  17. Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, Qian X, James SE, Raubitschek A, Forman SJ, Gopal AK, Pagel JM, Lindgren CG, Greenberg PD, Riddell SR, Press OW (2008) Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 112(6):2261–2271. doi:10.1182/blood-2007-12-128843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, Kamble RT, Bollard CM, Gee AP, Mei Z, Liu H, Grilley B, Rooney CM, Heslop HE, Brenner MK, Dotti G (2011) CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest 121(5):1822–1826. doi:10.1172/JCI46110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368(16):1509–1518. doi:10.1056/NEJMoa1215134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, Ambrose D, Grupp SA, Chew A, Zheng Z, Milone MC, Levine BL, Melenhorst JJ, June CH (2015) Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl med 7 (303):303ra139. doi:10.1126/scitranslmed.aac5415

  21. Turtle CJ, Hanafi LA, Berger C, Hudecek M, Pender B, Robinson E, Hawkins R, Chaney C, Cherian S, Chen X, Soma L, Wood B, Li D, Heimfeld S, Riddell SR, Maloney DG (2016) Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl med 8 (355):355ra116. doi:10.1126/scitranslmed.aaf8621

  22. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371(16):1507–1517. doi:10.1056/NEJMoa1407222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Till BG, Jensen MC, Wang J, Qian X, Gopal AK, Maloney DG, Lindgren CG, Lin Y, Pagel JM, Budde LE, Raubitschek A, Forman SJ, Greenberg PD, Riddell SR, Press OW (2012) CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood 119(17):3940–3950. doi:10.1182/blood-2011-10-387969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chmielewski M, Abken H (2015) TRUCKs: the fourth generation of CARs. Expert Opin Biol Ther 15(8):1145–1154. doi:10.1517/14712598.2015.1046430

    Article  CAS  PubMed  Google Scholar 

  25. Kalos M, June CH (2013) Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity 39(1):49–60. doi:10.1016/j.immuni.2013.07.002

    Article  CAS  PubMed  Google Scholar 

  26. Ruella M, June CH (2016) Chimeric antigen receptor T cells for B cell neoplasms: choose the right CAR for you. Curr Hematol Malig Rep 11(5):368–384. doi:10.1007/s11899-016-0336-z

    Article  PubMed  Google Scholar 

  27. Ruella M, Barrett DM, Kenderian SS, Shestova O, Hofmann TJ, Perazzelli J, Klichinsky M, Aikawa V, Nazimuddin F, Kozlowski M, Scholler J, Lacey SF, Melenhorst JJ, Morrissette JJ, Christian DA, Hunter CA, Kalos M, Porter DL, June CH, Grupp SA, Gill S (2016) Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J Clin Invest 126(10):3814–3826. doi:10.1172/JCI87366

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ruella M, Kenderian SS, Shestova O, Fraietta JA, Qayyum S, Zhang Q, Maus MV, Liu X, Nunez-Cruz S, Klichinsky M, Kawalekar OU, Milone M, Lacey SF, Mato A, Schuster SJ, Kalos M, June CH, Gill S, Wasik MA (2016) The addition of the BTK inhibitor Ibrutinib to anti-CD19 chimeric antigen receptor T cells (CART19) improves responses against mantle cell lymphoma. Clin Cancer Res 22(11):2684–2696. doi:10.1158/1078-0432.CCR-15-1527

    Article  CAS  PubMed  Google Scholar 

  29. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL (2015) T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385(9967):517–528. doi:10.1016/S0140-6736(14)61403-3

    Article  CAS  PubMed  Google Scholar 

  30. Greten TF, Jaffee EM (1999) Cancer vaccines. J Clin Oncol 17(3):1047–1060. doi:10.1200/JCO.1999.17.3.1047

    Article  CAS  PubMed  Google Scholar 

  31. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331(6024):1565–1570. doi:10.1126/science.1203486

    Article  CAS  PubMed  Google Scholar 

  32. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3(11):991–998. doi:10.1038/ni1102-991

    Article  CAS  PubMed  Google Scholar 

  33. Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22:329–360. doi:10.1146/annurev.immunol.22.012703.104803

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450(7171):903–907. doi:10.1038/nature06309

    Article  CAS  PubMed  Google Scholar 

  36. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD (2001) IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410(6832):1107–1111. doi:10.1038/35074122

    Article  CAS  PubMed  Google Scholar 

  37. Engel AM, Svane IM, Rygaard J, Werdelin O (1997) MCA sarcomas induced in scid mice are more immunogenic than MCA sarcomas induced in congenic, immunocompetent mice. Scand J Immunol 45(5):463–470

    Article  CAS  PubMed  Google Scholar 

  38. Svane IM, Engel AM, Nielsen MB, Ljunggren HG, Rygaard J, Werdelin O (1996) Chemically induced sarcomas from nude mice are more immunogenic than similar sarcomas from congenic normal mice. Eur J Immunol 26(8):1844–1850. doi:10.1002/eji.1830260827

    Article  CAS  PubMed  Google Scholar 

  39. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ (2011) Natural innate and adaptive immunity to cancer. Annu Rev Immunol 29:235–271. doi:10.1146/annurev-immunol-031210-101324

    Article  CAS  PubMed  Google Scholar 

  40. Smyth MJ, Dunn GP, Schreiber RD (2006) Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol 90:1–50. doi:10.1016/S0065-2776(06)90001-7

    Article  CAS  PubMed  Google Scholar 

  41. Zitvogel L, Tesniere A, Kroemer G (2006) Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol 6(10):715–727. doi:10.1038/nri1936

    Article  CAS  PubMed  Google Scholar 

  42. Khong HT, Restifo NP (2002) Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nat Immunol 3(11):999–1005. doi:10.1038/ni1102-999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, Ahmed R (1998) Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 188(12):2205–2213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gallimore A, Glithero A, Godkin A, Tissot AC, Pluckthun A, Elliott T, Hengartner H, Zinkernagel R (1998) Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J Exp Med 187(9):1383–1393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Brooks DG, Teyton L, Oldstone MB, McGavern DB (2005) Intrinsic functional dysregulation of CD4 T cells occurs rapidly following persistent viral infection. J Virol 79(16):10514–10527. doi:10.1128/JVI.79.16.10514-10527.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Oxenius A, Zinkernagel RM, Hengartner H (1998) Comparison of activation versus induction of unresponsiveness of virus-specific CD4+ and CD8+ T cells upon acute versus persistent viral infection. Immunity 9(4):449–457

    Article  CAS  PubMed  Google Scholar 

  47. Kaufmann DE, Kavanagh DG, Pereyra F, Zaunders JJ, Mackey EW, Miura T, Palmer S, Brockman M, Rathod A, Piechocka-Trocha A, Baker B, Zhu B, Le Gall S, Waring MT, Ahern R, Moss K, Kelleher AD, Coffin JM, Freeman GJ, Rosenberg ES, Walker BD (2007) Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat Immunol 8(11):1246–1254. doi:10.1038/ni1515

    Article  CAS  PubMed  Google Scholar 

  48. Urbani S, Amadei B, Fisicaro P, Tola D, Orlandini A, Sacchelli L, Mori C, Missale G, Ferrari C (2006) Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses. Hepatology 44(1):126–139. doi:10.1002/hep.21242

    Article  CAS  PubMed  Google Scholar 

  49. Kahan SM, Wherry EJ, Zajac AJ (2015) T cell exhaustion during persistent viral infections. Virology 479-480:180–193. doi:10.1016/j.virol.2014.12.033

    Article  CAS  PubMed  Google Scholar 

  50. Fuller MJ, Khanolkar A, Tebo AE, Zajac AJ (2004) Maintenance, loss, and resurgence of T cell responses during acute, protracted, and chronic viral infections. J Immunol 172(7):4204–4214

    Article  CAS  PubMed  Google Scholar 

  51. Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R (2003) Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 77(8):4911–4927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Virgin HW, Wherry EJ, Ahmed R (2009) Redefining chronic viral infection. Cell 138(1):30–50. doi:10.1016/j.cell.2009.06.036

    Article  CAS  PubMed  Google Scholar 

  53. Wherry EJ, Ahmed R (2004) Memory CD8 T-cell differentiation during viral infection. J Virol 78(11):5535–5545. doi:10.1128/JVI.78.11.5535-5545.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fuller MJ, Zajac AJ (2003) Ablation of CD8 and CD4 T cell responses by high viral loads. J Immunol 170(1):477–486

    Article  CAS  PubMed  Google Scholar 

  55. Agnellini P, Wolint P, Rehr M, Cahenzli J, Karrer U, Oxenius A (2007) Impaired NFAT nuclear translocation results in split exhaustion of virus-specific CD8+ T cell functions during chronic viral infection. Proc Natl Acad Sci U S A 104(11):4565–4570. doi:10.1073/pnas.0610335104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mackerness KJ, Cox MA, Lilly LM, Weaver CT, Harrington LE, Zajac AJ (2010) Pronounced virus-dependent activation drives exhaustion but sustains IFN-gamma transcript levels. J Immunol 185(6):3643–3651. doi:10.4049/jimmunol.1000841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, Adams WC, Precopio ML, Schacker T, Roederer M, Douek DC, Koup RA (2006) PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 203(10):2281–2292. doi:10.1084/jem.20061496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, Boulassel MR, Delwart E, Sepulveda H, Balderas RS, Routy JP, Haddad EK, Sekaly RP (2006) Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 12(10):1198–1202. doi:10.1038/nm1482

    Article  CAS  PubMed  Google Scholar 

  59. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, Mncube Z, Duraiswamy J, Zhu B, Eichbaum Q, Altfeld M, Wherry EJ, Coovadia HM, Goulder PJ, Klenerman P, Ahmed R, Freeman GJ, Walker BD (2006) PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443(7109):350–354. doi:10.1038/nature05115

    Article  CAS  PubMed  Google Scholar 

  60. Wherry EJ (2011) T cell exhaustion. Nat Immunol 12(6):492–499

    Article  CAS  PubMed  Google Scholar 

  61. Baitsch L, Fuertes-Marraco SA, Legat A, Meyer C, Speiser DE (2012) The three main stumbling blocks for anticancer T cells. Trends Immunol 33(7):364–372. doi:10.1016/j.it.2012.02.006

    Article  CAS  PubMed  Google Scholar 

  62. Schietinger A, Greenberg PD (2014) Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol 35(2):51–60. doi:10.1016/j.it.2013.10.001

    Article  CAS  PubMed  Google Scholar 

  63. Pauken KE, Wherry EJ (2015) Overcoming T cell exhaustion in infection and cancer. Trends Immunol 36(4):265–276. doi:10.1016/j.it.2015.02.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mellman I, Coukos G, Dranoff G (2011) Cancer immunotherapy comes of age. Nature 480(7378):480–489. doi:10.1038/nature10673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kim PS, Ahmed R (2010) Features of responding T cells in cancer and chronic infection. Curr Opin Immunol 22(2):223–230. doi:10.1016/j.coi.2010.02.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Crespo J, Sun H, Welling TH, Tian Z, Zou W (2013) T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol 25(2):214–221. doi:10.1016/j.coi.2012.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fourcade J, Kudela P, Sun Z, Shen H, Land SR, Lenzner D, Guillaume P, Luescher IF, Sander C, Ferrone S, Kirkwood JM, Zarour HM (2009) PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J Immunol 182(9):5240–5249. doi:10.4049/jimmunol.0803245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. doi:10.1038/nrc3239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nguyen LT, Ohashi PS (2015) Clinical blockade of PD1 and LAG3--potential mechanisms of action. Nat Rev Immunol 15(1):45–56. doi:10.1038/nri3790

    Article  CAS  PubMed  Google Scholar 

  70. Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, Kirkwood JM, Kuchroo V, Zarour HM Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med 207(10):2175–2186

    Google Scholar 

  71. Fourcade J, Sun Z, Pagliano O, Guillaume P, Luescher IF, Sander C, Kirkwood JM, Olive D, Kuchroo V, Zarour HM (2012) CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Res 72(4):887–896. doi:10.1158/0008-5472.CAN-11-2637

    Article  CAS  PubMed  Google Scholar 

  72. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 207(10):2187–2194

    Google Scholar 

  73. Jin HT, Anderson AC, Tan WG, West EE, Ha SJ, Araki K, Freeman GJ, Kuchroo VK, Ahmed R (2010) Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A 107(33):14733–14738. doi:10.1073/pnas.1009731107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kmieciak M, Worschech A, Nikizad H, Gowda M, Habibi M, Depcrynski A, Wang E, Godder K, Holt SE, Marincola FM, Manjili MH (2011) CD4+ T cells inhibit the neu-specific CD8+ T-cell exhaustion during the priming phase of immune responses against breast cancer. Breast Cancer Res Treat 126(2):385–394. doi:10.1007/s10549-010-0942-8

    Article  CAS  PubMed  Google Scholar 

  75. Sharpe AH, Abbas AK (2006) T-cell costimulation--biology, therapeutic potential, and challenges. N Engl J Med 355(10):973–975. doi:10.1056/NEJMp068087

    Article  CAS  PubMed  Google Scholar 

  76. Appleman LJ, Boussiotis VA (2003) T cell anergy and costimulation. Immunol Rev 192:161–180

    Article  CAS  PubMed  Google Scholar 

  77. Grosso JF, Jure-Kunkel MN (2013) CTLA-4 blockade in tumor models: an overview of preclinical and translational research. Cancer Immun 13:5

    PubMed  PubMed Central  Google Scholar 

  78. Egen JG, Kuhns MS, Allison JP (2002) CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol 3(7):611–618. doi:10.1038/ni0702-611

    Article  CAS  PubMed  Google Scholar 

  79. Collins AV, Brodie DW, Gilbert RJ, Iaboni A, Manso-Sancho R, Walse B, Stuart DI, van der Merwe PA, Davis SJ (2002) The interaction properties of costimulatory molecules revisited. Immunity 17(2):201–210

    Article  CAS  PubMed  Google Scholar 

  80. Yokosuka T, Kobayashi W, Takamatsu M, Sakata-Sogawa K, Zeng H, Hashimoto-Tane A, Yagita H, Tokunaga M, Saito T (2010) Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation. Immunity 33(3):326–339. doi:10.1016/j.immuni.2010.09.006

    Article  CAS  PubMed  Google Scholar 

  81. Schneider H, Valk E, da Rocha DS, Wei B, Rudd CE (2005) CTLA-4 up-regulation of lymphocyte function-associated antigen 1 adhesion and clustering as an alternate basis for coreceptor function. Proc Natl Acad Sci U S A 102(36):12861–12866. doi:10.1073/pnas.0505802102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, Baker J, Jeffery LE, Kaur S, Briggs Z, Hou TZ, Futter CE, Anderson G, Walker LS, Sansom DM (2011) Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332(6029):600–603. doi:10.1126/science.1202947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322(5899):271–275. doi:10.1126/science.1160062

    Article  CAS  PubMed  Google Scholar 

  84. Chuang E, Lee KM, Robbins MD, Duerr JM, Alegre ML, Hambor JE, Neveu MJ, Bluestone JA, Thompson CB (1999) Regulation of cytotoxic T lymphocyte-associated molecule-4 by Src kinases. J Immunol 162(3):1270–1277

    CAS  PubMed  Google Scholar 

  85. Carreno BM, Bennett F, Chau TA, Ling V, Luxenberg D, Jussif J, Baroja ML, Madrenas J (2000) CTLA-4 (CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression. J Immunol 165(3):1352–1356

    Article  CAS  PubMed  Google Scholar 

  86. Cinek T, Sadra A, Imboden JB (2000) Cutting edge: tyrosine-independent transmission of inhibitory signals by CTLA-4. J Immunol 164(1):5–8

    Article  CAS  PubMed  Google Scholar 

  87. van der Merwe PA, Bodian DL, Daenke S, Linsley P, Davis SJ (1997) CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J Exp Med 185(3):393–403

    Article  PubMed  PubMed Central  Google Scholar 

  88. Acuto O, Michel F (2003) CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol 3(12):939–951. doi:10.1038/nri1248

    Article  CAS  PubMed  Google Scholar 

  89. Alegre ML, Noel PJ, Eisfelder BJ, Chuang E, Clark MR, Reiner SL, Thompson CB (1996) Regulation of surface and intracellular expression of CTLA4 on mouse T cells. J Immunol 157(11):4762–4770

    CAS  PubMed  Google Scholar 

  90. Harper K, Balzano C, Rouvier E, Mattei MG, Luciani MF, Golstein P (1991) CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. J Immunol 147(3):1037–1044

    CAS  PubMed  Google Scholar 

  91. Lindsten T, Lee KP, Harris ES, Petryniak B, Craighead N, Reynolds PJ, Lombard DB, Freeman GJ, Nadler LM, Gray GS et al (1993) Characterization of CTLA-4 structure and expression on human T cells. J Immunol 151(7):3489–3499

    CAS  PubMed  Google Scholar 

  92. Freeman GJ, Lombard DB, Gimmi CD, Brod SA, Lee K, Laning JC, Hafler DA, Dorf ME, Gray GS, Reiser H et al (1992) CTLA-4 and CD28 mRNA are coexpressed in most T cells after activation. Expression of CTLA-4 and CD28 mRNA does not correlate with the pattern of lymphokine production. J Immunol 149(12):3795–3801

    CAS  PubMed  Google Scholar 

  93. Linsley PS, Greene JL, Tan P, Bradshaw J, Ledbetter JA, Anasetti C, Damle NK (1992) Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med 176(6):1595–1604

    Article  CAS  PubMed  Google Scholar 

  94. Walunas TL, Bakker CY, Bluestone JA (1996) CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med 183(6):2541–2550

    Article  CAS  PubMed  Google Scholar 

  95. Kaufman KA, Bowen JA, Tsai AF, Bluestone JA, Hunt JS, Ober C (1999) The CTLA-4 gene is expressed in placental fibroblasts. Mol Hum Reprod 5(1):84–87

    Article  CAS  PubMed  Google Scholar 

  96. Ling V, Munroe RC, Murphy EA, Gray GS (1998) Embryonic stem cells and embryoid bodies express lymphocyte costimulatory molecules. Exp Cell Res 241(1):55–65. doi:10.1006/excr.1998.4055

    Article  CAS  PubMed  Google Scholar 

  97. Pioli C, Gatta L, Ubaldi V, Doria G (2000) Inhibition of IgG1 and IgE production by stimulation of the B cell CTLA-4 receptor. J Immunol 165(10):5530–5536

    Article  CAS  PubMed  Google Scholar 

  98. Pistillo MP, Tazzari PL, Palmisano GL, Pierri I, Bolognesi A, Ferlito F, Capanni P, Polito L, Ratta M, Pileri S, Piccioli M, Basso G, Rissotto L, Conte R, Gobbi M, Stirpe F, Ferrara GB (2003) CTLA-4 is not restricted to the lymphoid cell lineage and can function as a target molecule for apoptosis induction of leukemic cells. Blood 101(1):202–209. doi:10.1182/blood-2002-06-1668

    Article  CAS  PubMed  Google Scholar 

  99. Nakamoto N, Kaplan DE, Coleclough J, Li Y, Valiga ME, Kaminski M, Shaked A, Olthoff K, Gostick E, Price DA, Freeman GJ, Wherry EJ, Chang KM (2008) Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization. Gastroenterology 134(7):1927–1937, 1937 e1921–e1922. doi:10.1053/j.gastro.2008.02.033

  100. Liu Y, Yu Y, Yang S, Zeng B, Zhang Z, Jiao G, Zhang Y, Cai L, Yang R (2009) Regulation of arginase I activity and expression by both PD-1 and CTLA-4 on the myeloid-derived suppressor cells. Cancer Immunol Immunother 58(5):687–697. doi:10.1007/s00262-008-0591-5

    Article  CAS  PubMed  Google Scholar 

  101. Nishimura H, Agata Y, Kawasaki A, Sato M, Imamura S, Minato N, Yagita H, Nakano T, Honjo T (1996) Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. Int Immunol 8(5):773–780

    Article  CAS  PubMed  Google Scholar 

  102. Oestreich KJ, Yoon H, Ahmed R, Boss JM (2008) NFATc1 regulates PD-1 expression upon T cell activation. J Immunol 181(7):4832–4839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Staron MM, Gray SM, Marshall HD, Parish IA, Chen JH, Perry CJ, Cui G, Li MO, Kaech SM (2014) The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T cells during chronic infection. Immunity 41(5):802–814. doi:10.1016/j.immuni.2014.10.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mathieu M, Cotta-Grand N, Daudelin JF, Thebault P, Labrecque N (2013) Notch signaling regulates PD-1 expression during CD8(+) T-cell activation. Immunol Cell Biol 91(1):82–88. doi:10.1038/icb.2012.53

    Article  CAS  PubMed  Google Scholar 

  105. Kao C, Oestreich KJ, Paley MA, Crawford A, Angelosanto JM, Ali MA, Intlekofer AM, Boss JM, Reiner SL, Weinmann AS, Wherry EJ (2011) Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection. Nat Immunol 12(7):663–671. doi:10.1038/ni.2046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291(5502):319–322. doi:10.1126/science.291.5502.319

    Article  CAS  PubMed  Google Scholar 

  107. Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11(2):141–151

    Article  CAS  PubMed  Google Scholar 

  108. Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K, Azuma M, Yagita H (2002) Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 169(10):5538–5545

    Article  CAS  PubMed  Google Scholar 

  109. Zhong X, Tumang JR, Gao W, Bai C, Rothstein TL (2007) PD-L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for V(H)11/V(H)12 and phosphatidylcholine binding. Eur J Immunol 37(9):2405–2410. doi:10.1002/eji.200737461

    Article  CAS  PubMed  Google Scholar 

  110. Nurieva R, Thomas S, Nguyen T, Martin-Orozco N, Wang Y, Kaja MK, Yu XZ, Dong C (2006) T-cell tolerance or function is determined by combinatorial costimulatory signals. EMBO J 25(11):2623–2633. doi:10.1038/sj.emboj.7601146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N (2002) Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 99(19):12293–12297. doi:10.1073/pnas.192461099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gokbuget N, O’Brien S, Wang K, Wang T, Paccagnella ML, Sleight B, Vandendries E, Advani AS (2016) Inotuzumab Ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 375(8):740–753. doi:10.1056/NEJMoa1509277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465. doi:10.1056/NEJMoa1200694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Salazar LG, Lu H, Reichow JL, Childs JS, Coveler AL, Higgins DM, Waisman J, Allison KH, Dang Y, Disis ML (2017) Topical Imiquimod plus nab-paclitaxel for breast cancer cutaneous metastases: a phase 2 clinical trial. JAMA Oncol. doi:10.1001/jamaoncol.2016.6007

  115. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520. doi:10.1056/NEJMoa1500596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (2000) BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 14(8):927–939

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Parsons R, Li GM, Longley MJ, Fang WH, Papadopoulos N, Jen J, de la Chapelle A, Kinzler KW, Vogelstein B, Modrich P (1993) Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 75(6):1227–1236

    Article  CAS  PubMed  Google Scholar 

  118. Loeb LA (1994) Microsatellite instability: marker of a mutator phenotype in cancer. Cancer Res 54(19):5059–5063

    CAS  PubMed  Google Scholar 

  119. Devaud N, Gallinger S (2013) Chemotherapy of MMR-deficient colorectal cancer. Familial Cancer 12(2):301–306. doi:10.1007/s10689-013-9633-z

    Article  CAS  PubMed  Google Scholar 

  120. Westdorp H, Fennemann FL, Weren RD, Bisseling TM, Ligtenberg MJ, Figdor CG, Schreibelt G, Hoogerbrugge N, Wimmers F, de Vries IJ (2016) Opportunities for immunotherapy in microsatellite instable colorectal cancer. Cancer Immunol Immunother 65(10):1249–1259. doi:10.1007/s00262-016-1832-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Dudley JC, Lin MT, Le DT, Eshleman JR (2016) Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res 22(4):813–820. doi:10.1158/1078-0432.CCR-15-1678

    Article  CAS  PubMed  Google Scholar 

  122. Yee CJ, Roodi N, Verrier CS, Parl FF (1994) Microsatellite instability and loss of heterozygosity in breast cancer. Cancer Res 54(7):1641–1644

    CAS  PubMed  Google Scholar 

  123. Shaw JA, Walsh T, Chappell SA, Carey N, Johnson K, Walker RA (1996) Microsatellite instability in early sporadic breast cancer. Br J Cancer 73(11):1393–1397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bourdais R, Rousseau B, Pujals A, Boussion H, Joly C, Guillemin A, Baumgaertner I, Neuzillet C, Tournigand C (2017) Polymerase proofreading domain mutations: new opportunities for immunotherapy in hypermutated colorectal cancer beyond MMR deficiency. Crit Rev Oncol Hematol 113:242–248. doi:10.1016/j.critrevonc.2017.03.027

    Article  PubMed  Google Scholar 

  125. Bupathi M, Wu C (2016) Biomarkers for immune therapy in colorectal cancer: mismatch-repair deficiency and others. J Gastrointest Oncol 7(5):713–720. doi:10.21037/jgo.2016.07.03

  126. Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271(5256):1734–1736

    Article  CAS  PubMed  Google Scholar 

  127. van Elsas A, Hurwitz AA, Allison JP (1999) Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med 190(3):355–366

    Article  PubMed  PubMed Central  Google Scholar 

  128. Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, Davis T, Henry-Spires R, MacRae S, Willman A, Padera R, Jaklitsch MT, Shankar S, Chen TC, Korman A, Allison JP, Dranoff G (2003) Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A 100(8):4712–4717. doi:10.1073/pnas.0830997100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, Macrae S, Nelson M, Canning C, Lowy I, Korman A, Lautz D, Russell S, Jaklitsch MT, Ramaiya N, Chen TC, Neuberg D, Allison JP, Mihm MC, Dranoff G (2008) Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A 105(8):3005–3010. doi:10.1073/pnas.0712237105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, Restifo NP, Haworth LR, Seipp CA, Freezer LJ, Morton KE, Mavroukakis SA, Duray PH, Steinberg SM, Allison JP, Davis TA, Rosenberg SA (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 100(14):8372–8377. doi:10.1073/pnas.1533209100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ribas A (2008) Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with tremelimumab (CP-675,206). Oncologist 13(Suppl 4):10–15. doi:10.1634/theoncologist.13-S4-10

    Article  CAS  PubMed  Google Scholar 

  132. McArthur HL, Diab A, Page DB, Yuan J, Solomon SB, Sacchini V, Comstock C, Durack JC, Maybody M, Sung J, Ginsberg A, Wong P, Barlas A, Dong Z, Zhao C, Blum B, Patil S, Neville D, Comen EA, Morris EA, Kotin A, Brogi E, Wen YH, Morrow M, Lacouture ME, Sharma P, Allison JP, Hudis CA, Wolchok JD, Norton L (2016) A pilot study of preoperative single-dose Ipilimumab and/or Cryoablation in women with early-stage breast cancer with comprehensive immune profiling. Clin Cancer Res 22(23):5729–5737. doi:10.1158/1078-0432.CCR-16-0190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Vonderheide RH, LoRusso PM, Khalil M, Gartner EM, Khaira D, Soulieres D, Dorazio P, Trosko JA, Ruter J, Mariani GL, Usari T, Domchek SM (2010) Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells. Clin Cancer Res 16(13):3485–3494. doi:10.1158/1078-0432.CCR-10-0505

    Article  CAS  PubMed  Google Scholar 

  134. Mittendorf EA, Philips AV, Meric-Bernstam F, Qiao N, Wu Y, Harrington S, Su X, Wang Y, Gonzalez-Angulo AM, Akcakanat A, Chawla A, Curran M, Hwu P, Sharma P, Litton JK, Molldrem JJ, Alatrash G (2014) PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2(4):361–370. doi:10.1158/2326-6066.CIR-13-0127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Metivier D, Larochette N, van Endert P, Ciccosanti F, Piacentini M, Zitvogel L, Kroemer G (2007) Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 13(1):54–61. doi:10.1038/nm1523

    Article  CAS  PubMed  Google Scholar 

  136. Kroemer G, Galluzzi L, Kepp O, Zitvogel L (2013) Immunogenic cell death in cancer therapy. Annu Rev Immunol 31:51–72. doi:10.1146/annurev-immunol-032712-100008

    Article  CAS  PubMed  Google Scholar 

  137. Bracci L, Schiavoni G, Sistigu A, Belardelli F (2014) Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ 21(1):15–25. doi:10.1038/cdd.2013.67

    Article  CAS  PubMed  Google Scholar 

  138. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P, Yang H, Amigorena S, Ryffel B, Barrat FJ, Saftig P, Levi F, Lidereau R, Nogues C, Mira JP, Chompret A, Joulin V, Clavel-Chapelon F, Bourhis J, Andre F, Delaloge S, Tursz T, Kroemer G, Zitvogel L (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13(9):1050–1059. doi:10.1038/nm1622

    Article  CAS  PubMed  Google Scholar 

  139. Apetoh L, Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Piacentini M, Kroemer G, Zitvogel L (2007) Immunogenic chemotherapy: discovery of a critical protein through proteomic analyses of tumor cells. Cancer Genomics Proteomics 4(2):65–70

    CAS  PubMed  Google Scholar 

  140. Obeid M, Panaretakis T, Tesniere A, Joza N, Tufi R, Apetoh L, Ghiringhelli F, Zitvogel L, Kroemer G (2007) Leveraging the immune system during chemotherapy: moving calreticulin to the cell surface converts apoptotic death from “silent” to immunogenic. Cancer Res 67(17):7941–7944. doi:10.1158/0008-5472.CAN-07-1622

    Article  CAS  PubMed  Google Scholar 

  141. Tesniere A, Panaretakis T, Kepp O, Apetoh L, Ghiringhelli F, Zitvogel L, Kroemer G (2008) Molecular characteristics of immunogenic cancer cell death. Cell Death Differ 15(1):3–12. doi:10.1038/sj.cdd.4402269

    Article  CAS  PubMed  Google Scholar 

  142. Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, Karantza V, Buisseret L (2016) Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol 34(21):2460–2467. doi:10.1200/JCO.2015.64.8931

    Article  CAS  PubMed  Google Scholar 

  143. Rita Nanda MCL, Yau C, Asare S, Hylton N, Van’t Veer L, Jane Perlmutter, Wallace AM, Chien AJ, Forero-Torres A, Ellis E, Han H, Clark AS, Albain KS, Boughey JC, Elias AD, Berry DA, Yee D, DeMichele A, Esserman L; I-SPY Network, The University of Chicago, Chicago, IL; The University of Texas MD Anderson Cancer Center, Houston, TX; Mayo Clinic, Rochester, MN; Masonic Cancer Center, University of Minnesota, Minneapolis, MN; Abramson Cancer Center, Philadelphia, PA; Buck Institute for Age Research, Novato, CA; Quantum Leap Health Care Collaborative, San Francisco, CA; UC San Francisco, San Francisco, CA; University of California, San Francisco, San Francisco, CA; Gemini Group, Ann Arbor, MI; University of California San Diego Moores Cancer Center, La Jolla, CA; University of Alabama at Birmingham, Birmingham, AL; Swedish Cancer Inst, Seattle, WA; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Hospital of the University of Pennsylvania, Philadelphia, PA; Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, IL; University of Colorado Comprehensive Cancer Center, Aurora, CO (2017) Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): results from I-SPY 2. Paper presented at the 2017 ASCO annual meeting, Chicago, June 5

    Google Scholar 

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  1. Department of Medical Oncology, The First Affiliated Hospital, Henan University Cancer Center, School of Medicine, Henan University, Kaifeng, People’s Republic of China

    Xia Bu & Yihui Yao

  2. Department of Hematology, The First Affiliated Hospital, Henan University Cancer Center, School of Medicine, Henan University, Kaifeng, People’s Republic of China

    Xiaoyu Li

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  1. Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Erwei Song

  2. Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Hai Hu

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Bu, X., Yao, Y., Li, X. (2017). Immune Checkpoint Blockade in Breast Cancer Therapy. In: Song, E., Hu, H. (eds) Translational Research in Breast Cancer. Advances in Experimental Medicine and Biology, vol 1026. Springer, Singapore. https://doi.org/10.1007/978-981-10-6020-5_18

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