Immunotherapy in Head and Neck Squamous Cell Carcinoma (HNSCC)

  • Jennifer Moy
  • Robert L. FerrisEmail author
Part of the Current Cancer Research book series (CUCR)


Based on its ability to restore key signaling pathways of the host immune system and thus to counteract immune escape by malignant cells, cancer immunotherapy is now at the forefront of cancer research in the treatment of head and neck squamous cell carcinoma (HNSCC). Understanding how tumors evade immune recognition and attack, through strategies that include reducing inherent immunogenicity, dysregulating immune checkpoints, and producing an immunosuppressive tumor microenvironment, will allow the development of novel therapeutic agents to manipulate the immune response. Various forms of immunotherapy are in preclinical trials, including vaccines, oncolytic viruses, and adoptive cell transfer, with the most promising clinical results thus far associated with the use of monoclonal antibodies. This chapter will review the mechanisms of immune escape, and will describe ongoing preclinical and clinical studies, and their implications for immunotherapy in HNSCC.


NK cells EGFR PD-1 PD-L1 Cetuximab Immune checkpoint receptors Programmed cell death 1 


Financial Support

This work was supported by the National Institutes of Health grants R01 DE19727, P50 CA097190, and CA110249 U10 CA021115 (PITTDEVRF-00) and University of Pittsburgh Cancer Center Support Grant P30CA047904.


  1. 1.
    Ehrlich P. In: Himmelweit EI, editor. The collected papers of Paul Ehrlich. London: Pergamon Press; F1957.Google Scholar
  2. 2.
    Badoual C, et al. Better understanding tumor-host interaction in head and neck cancer to improve the design and development of immunotherapeutic strategies. Head Neck. 2010;32(7):946–58.PubMedGoogle Scholar
  3. 3.
    Allen CT, et al. The clinical implications of antitumor immunity in head and neck cancer. Laryngoscope. 2012;122(1):144–57.CrossRefPubMedGoogle Scholar
  4. 4.
    Kuss I, et al. Decreased absolute counts of T lymphocyte subsets and their relation to disease in squamous cell carcinoma of the head and neck. Clin Cancer Res. 2004;10(11):3755–62.CrossRefPubMedGoogle Scholar
  5. 5.
    Dasgupta S, et al. Inhibition of NK cell activity through TGF-beta 1 by down-regulation of NKG2D in a murine model of head and neck cancer. J Immunol. 2005;175(8):5541–50.CrossRefPubMedGoogle Scholar
  6. 6.
    Young MR, et al. Mechanisms of immune suppression in patients with head and neck cancer: influence on the immune infiltrate of the cancer. Int J Cancer. 1996;67(3):333–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Lopez-Albaitero A, et al. Role of antigen-processing machinery in the in vitro resistance of squamous cell carcinoma of the head and neck cells to recognition by CTL. J Immunol. 2006;176(6):3402–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Ferris RL, Whiteside TL, Ferrone S. Immune escape associated with functional defects in antigen-processing machinery in head and neck cancer. Clin Cancer Res. 2006;12(13):3890–5.CrossRefPubMedGoogle Scholar
  9. 9.
    Bindon C, et al. Clearance rates and systemic effects of intravenously administered interleukin 2 (IL-2) containing preparations in human subjects. Br J Cancer. 1983;47(1):123–33.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Kirkwood JM, et al. Comparison of intramuscular and intravenous recombinant alpha-2 interferon in melanoma and other cancers. Ann Intern Med. 1985;103(1):32–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Lienard D, et al. High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol. 1992;10(1):52–60.CrossRefPubMedGoogle Scholar
  12. 12.
    Jonasch E, Haluska FG. Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncologist. 2001;6(1):34–55.CrossRefGoogle Scholar
  13. 13.
    To, S.Q, Knower KC, Clyne CD. Origins and actions of tumor necrosis factor alpha in postmenopausal breast cancer. J Interf Cytokine Res. 2013;33(7):335–45.CrossRefGoogle Scholar
  14. 14.
    Vermorken JB, et al. Overview of the efficacy of cetuximab in recurrent and/or metastatic squamous cell carcinoma of the head and neck in patients who previously failed platinum-based therapies. Cancer. 2008;112(12):2710–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Scott AM, Allison JP, Wolchok JD. Monoclonal antibodies in cancer therapy. Cancer Immun. 2012;12:14.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Rao SD, Fury MG, Pfister DG. Molecular-targeted therapies in head and neck cancer. Semin Radiat Oncol. 2012;22(3):207–13.CrossRefPubMedGoogle Scholar
  17. 17.
    Page DB, et al. Immune modulation in cancer with antibodies. Annu Rev Med. 2014;65:185–202.CrossRefPubMedGoogle Scholar
  18. 18.
    Whang SN, Filippova M, Duerksen-Hughes P. Recent progress in therapeutic treatments and screening strategies for the prevention and treatment of HPV-associated head and neck Cancer. Virus. 2015;7(9):5040–65.CrossRefGoogle Scholar
  19. 19.
    Lott JB. Oncolytic viruses: a new paradigm for treatment of head and neck cancer. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113(2):155–60.CrossRefPubMedGoogle Scholar
  20. 20.
    Jiang P, et al. Adoptive cell transfer after chemotherapy enhances survival in patients with resectable HNSCC. Int Immunopharmacol. 2015;28(1):208–14.CrossRefPubMedGoogle Scholar
  21. 21.
    Lynch TJ, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39.CrossRefPubMedGoogle Scholar
  22. 22.
    Lane DP. Cancer. p53, guardian of the genome. Nature. 1992;358(6381):15–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Burnet FM. The concept of immunological surveillance. Prog Exp Tumor Res. 1970;13:1–27.CrossRefPubMedGoogle Scholar
  24. 24.
    Herberman RB, Holden HT. Natural cell-mediated immunity. Adv Cancer Res. 1978;27:305–77.CrossRefPubMedGoogle Scholar
  25. 25.
    Dunn GP, et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3(11):991–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Bhatia S, et al. Solid cancers after bone marrow transplantation. J Clin Oncol. 2001;19(2):464–71.CrossRefPubMedGoogle Scholar
  27. 27.
    Haigentz M Jr. Aerodigestive cancers in HIV infection. Curr Opin Oncol. 2005;17(5):474–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011;331(6024):1565–70.CrossRefGoogle Scholar
  29. 29.
    Ferris RL, Hunt JL, Ferrone S. Human leukocyte antigen (HLA) class I defects in head and neck cancer: molecular mechanisms and clinical significance. Immunol Res. 2005;33(2):113–33.CrossRefPubMedGoogle Scholar
  30. 30.
    Mizukami Y, et al. Downregulation of HLA class I molecules in the tumour is associated with a poor prognosis in patients with oesophageal squamous cell carcinoma. Br J Cancer. 2008;99(9):1462–7.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Ogino T, et al. HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker. Cancer Res. 2006;66(18):9281–9.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Concha-Benavente F, et al. Immunological and clinical significance of HLA class I antigen processing machinery component defects in malignant cells. Oral Oncol. 2016;58:52–8.PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Chatrchyan S, et al. Search for invisible decays of Higgs bosons in the vector boson fusion and associated ZH production modes. Eur Phys J C Part Fields. 2014;74(8):2980.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Chatrchyan S, et al. Measurement of WZ and ZZ production in pp collisions at [formula: see text] in final states with b-tagged jets. Eur Phys J C Part Fields. 2014;74(8):2973.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Bauman JE, Ferris RL. Integrating novel therapeutic monoclonal antibodies into the management of head and neck cancer. Cancer. 2014;120(5):624–32.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Andrews LP, et al. LAG3 (CD223) as a cancer immunotherapy target. Immunol Rev. 2017;276(1):80–96.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Anderson AC. Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol Res. 2014;2(5):393–8.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Benson DM Jr, Caligiuri MA. Killer immunoglobulin-like receptors and tumor immunity. Cancer Immunol Res. 2014;2(2):99–104.PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Ferris RL. Immunology and immunotherapy of head and neck Cancer. J Clin Oncol. 2015;33(29):3293–304.PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Baruah P, et al. Decreased levels of alternative co-stimulatory receptors OX40 and 4-1BB characterise T cells from head and neck cancer patients. Immunobiology. 2012;217(7):669–75.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev. 2009;229(1):12–26.PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992;71(7):1065–8.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Honeychurch J, et al. Immuno-regulatory antibodies for the treatment of cancer. Expert Opin Biol Ther. 2015;15(6):787–801.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Alegre ML, et al. Regulation of surface and intracellular expression of CTLA4 on mouse T cells. J Immunol. 1996;157(11):4762–70.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Chambers CA, Kuhns MS, Allison JP. Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses. Proc Natl Acad Sci U S A. 1999;96(15):8603–8.PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity. 2002;16(1):23–35.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Takahashi T, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192(2):303–10.PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Wing K, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271–5.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Linsley PS, et al. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity. 1994;1(9):793–801.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Qureshi OS, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011;332(6029):600–3.PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Oderup C, et al. Cytotoxic T lymphocyte antigen-4-dependent down-modulation of costimulatory molecules on dendritic cells in CD4+ CD25+ regulatory T-cell-mediated suppression. Immunology. 2006;118(2):240–9.PubMedCentralCrossRefPubMedGoogle Scholar
  52. 52.
    Keir ME, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.CrossRefPubMedGoogle Scholar
  53. 53.
    Keir ME, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203(4):883–95.PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    Liang SC, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol. 2003;33(10):2706–16.CrossRefPubMedGoogle Scholar
  55. 55.
    Latchman Y, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261–8.CrossRefPubMedGoogle Scholar
  56. 56.
    Freeman GJ, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–34.PubMedCentralCrossRefPubMedGoogle Scholar
  57. 57.
    Eppihimer MJ, et al. Expression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells. Microcirculation. 2002;9(2):133–45.PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    Butte MJ, et al. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27(1):111–22.PubMedCentralCrossRefPubMedGoogle Scholar
  59. 59.
    Parsa AT, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13(1):84–8.CrossRefPubMedGoogle Scholar
  60. 60.
    Concha-Benavente F, et al. Identification of the cell-intrinsic and -extrinsic pathways downstream of EGFR and IFNgamma that induce PD-L1 expression in head and neck Cancer. Cancer Res. 2016;76(5):1031–43.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Seiwert TY, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016;17(7):956–65.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12(6):492–9.CrossRefPubMedGoogle Scholar
  63. 63.
    Francisco LM, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206(13):3015–29.PubMedCentralCrossRefPubMedGoogle Scholar
  64. 64.
    Lowther DE, et al. PD-1 marks dysfunctional regulatory T cells in malignant gliomas. JCI Insight. 2016;1(5):e85935.PubMedCentralCrossRefPubMedGoogle Scholar
  65. 65.
    Badoual C, et al. PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. 2013;73(1):128–38.CrossRefPubMedGoogle Scholar
  66. 66.
    Ukpo OC, Thorstad WL, Lewis JS Jr. B7-H1 expression model for immune evasion in human papillomavirus-related oropharyngeal squamous cell carcinoma. Head Neck Pathol. 2013;7(2):113–21.CrossRefPubMedGoogle Scholar
  67. 67.
    Lyford-Pike S, et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013;73(6):1733–41.PubMedCentralCrossRefPubMedGoogle Scholar
  68. 68.
    Goldberg MV, Drake CG. LAG-3 in Cancer immunotherapy. Curr Top Microbiol Immunol. 2011;344:269–78.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Camisaschi C, et al. Alternative activation of human plasmacytoid DCs in vitro and in melanoma lesions: involvement of LAG-3. J Invest Dermatol. 2014;134(7):1893–902.CrossRefPubMedGoogle Scholar
  70. 70.
    Grosso JF, et al. Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J Immunol. 2009;182(11):6659–69.PubMedCentralCrossRefPubMedGoogle Scholar
  71. 71.
    Woo SR, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72(4):917–27.CrossRefPubMedGoogle Scholar
  72. 72.
    Sakuishi K, et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207(10):2187–94.PubMedCentralCrossRefPubMedGoogle Scholar
  73. 73.
    Zhou Q, et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood. 2011;117(17):4501–10.PubMedCentralCrossRefPubMedGoogle Scholar
  74. 74.
    Fourcade J, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207(10):2175–86.PubMedCentralCrossRefPubMedGoogle Scholar
  75. 75.
    Gao X, et al. TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS One. 2012;7(2):e30676.PubMedCentralCrossRefPubMedGoogle Scholar
  76. 76.
    Yang ZZ, et al. IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J Clin Invest. 2012;122(4):1271–82.PubMedCentralCrossRefPubMedGoogle Scholar
  77. 77.
    da Silva IP, et al. Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol Res. 2014;2(5):410–22.PubMedCentralCrossRefPubMedGoogle Scholar
  78. 78.
    Jie HB, et al. Intratumoral regulatory T cells upregulate immunosuppressive molecules in head and neck cancer patients. Br J Cancer. 2013;109(10):2629–35.PubMedCentralCrossRefPubMedGoogle Scholar
  79. 79.
    Herberman RB, et al. Role of interferon in augmentation of natural and antibody-dependent cell-mediated cytotoxicity. Cancer Treat Rep. 1978;62(11):1893–6.PubMedGoogle Scholar
  80. 80.
    Sakuishi K, et al. TIM3+FOXP3+ regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer. Oncoimmunology. 2013;2(4):e23849.PubMedCentralCrossRefPubMedGoogle Scholar
  81. 81.
    Thielens A, Vivier E, Romagne F. NK cell MHC class I specific receptors (KIR): from biology to clinical intervention. Curr Opin Immunol. 2012;24(2):239–45.CrossRefPubMedGoogle Scholar
  82. 82.
    Moesta AK, Parham P. Diverse functionality among human NK cell receptors for the C1 epitope of HLA-C: KIR2DS2, KIR2DL2, and KIR2DL3. Front Immunol. 2012;3:336.PubMedCentralCrossRefPubMedGoogle Scholar
  83. 83.
    Yusa S, Campbell KS. Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) can play a direct role in the inhibitory function of killer cell Ig-like receptors in human NK cells. J Immunol. 2003;170(9):4539–47.CrossRefPubMedGoogle Scholar
  84. 84.
    Purdy AK, Campbell KS. Natural killer cells and cancer: regulation by the killer cell Ig-like receptors (KIR). Cancer Biol Ther. 2009;8(23):2211–20.CrossRefPubMedGoogle Scholar
  85. 85.
    Besson C, et al. Association of killer cell immunoglobulin-like receptor genes with Hodgkin's lymphoma in a familial study. PLoS One. 2007;2(5):e406.PubMedCentralCrossRefPubMedGoogle Scholar
  86. 86.
    Verheyden S, Bernier M, Demanet C. Identification of natural killer cell receptor phenotypes associated with leukemia. Leukemia. 2004;18(12):2002–7.CrossRefPubMedGoogle Scholar
  87. 87.
    Mandal R, et al. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight. 2016;1(17):e89829.PubMedCentralCrossRefPubMedGoogle Scholar
  88. 88.
    Pollok KE, et al. Inducible T cell antigen 4-1BB. Analysis of expression and function. J Immunol. 1993;150(3):771–81.PubMedGoogle Scholar
  89. 89.
    Melero I, et al. NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies. Cell Immunol. 1998;190(2):167–72.CrossRefPubMedGoogle Scholar
  90. 90.
    Lynch DH. The promise of 4-1BB (CD137)-mediated immunomodulation and the immunotherapy of cancer. Immunol Rev. 2008;222:277–86.CrossRefPubMedGoogle Scholar
  91. 91.
    Vetto JT, et al. Presence of the T-cell activation marker OX-40 on tumor infiltrating lymphocytes and draining lymph node cells from patients with melanoma and head and neck cancers. Am J Surg. 1997;174(3):258–65.CrossRefPubMedGoogle Scholar
  92. 92.
    Bell RB, et al. OX40 signaling in head and neck squamous cell carcinoma: overcoming immunosuppression in the tumor microenvironment. Oral Oncol. 2016;52:1–10.CrossRefPubMedGoogle Scholar
  93. 93.
    Eliopoulos AG, Young LS. The role of the CD40 pathway in the pathogenesis and treatment of cancer. Curr Opin Pharmacol. 2004;4(4):360–7.CrossRefPubMedGoogle Scholar
  94. 94.
    van Kooten C, Banchereau J. CD40-CD40 ligand. J Leukoc Biol. 2000;67(1):2–17.CrossRefPubMedGoogle Scholar
  95. 95.
    Cao W, et al. CD40 function in squamous cell cancer of the head and neck. Oral Oncol. 2005;41(5):462–9.CrossRefPubMedGoogle Scholar
  96. 96.
    Posner MR, et al. Surface membrane-expressed CD40 is present on tumor cells from squamous cell cancer of the head and neck in vitro and in vivo and regulates cell growth in tumor cell lines. Clin Cancer Res. 1999;5(8):2261–70.PubMedGoogle Scholar
  97. 97.
    Funakoshi S, et al. Inhibition of human B-cell lymphoma growth by CD40 stimulation. Blood. 1994;83(10):2787–94.PubMedGoogle Scholar
  98. 98.
    von Leoprechting A, et al. Stimulation of CD40 on immunogenic human malignant melanomas augments their cytotoxic T lymphocyte-mediated lysis and induces apoptosis. Cancer Res. 1999;59(6):1287–94.Google Scholar
  99. 99.
    Sathawane D, et al. Monocyte CD40 expression in head and neck squamous cell carcinoma (HNSCC). Hum Immunol. 2013;74(1):1–5.CrossRefPubMedGoogle Scholar
  100. 100.
    Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–99.PubMedCentralCrossRefPubMedGoogle Scholar
  101. 101.
    Jebreel A, et al. Investigation of interleukin 10, 12 and 18 levels in patients with head and neck cancer. J Laryngol Otol. 2007;121(3):246–52.CrossRefPubMedGoogle Scholar
  102. 102.
    Moutsopoulos NM, Wen J, Wahl SM. TGF-beta and tumors--an ill-fated alliance. Curr Opin Immunol. 2008;20(2):234–40.PubMedCentralCrossRefPubMedGoogle Scholar
  103. 103.
    Mannino MH, et al. The paradoxical role of IL-10 in immunity and cancer. Cancer Lett. 2015;367(2):103–7.CrossRefPubMedGoogle Scholar
  104. 104.
    Harris SG, et al. Prostaglandins as modulators of immunity. Trends Immunol. 2002;23(3):144–50.CrossRefPubMedGoogle Scholar
  105. 105.
    Snyderman CH, et al. Prognostic significance of prostaglandin E2 production in fresh tissues of head and neck cancer patients. Head Neck. 1995;17(2):108–13.CrossRefPubMedGoogle Scholar
  106. 106.
    Camacho M, et al. Prostaglandin E(2) pathway in head and neck squamous cell carcinoma. Head Neck. 2008;30(9):1175–81.CrossRefPubMedGoogle Scholar
  107. 107.
    Seiwert TY, Cohen EE. Targeting angiogenesis in head and neck cancer. Semin Oncol. 2008;35(3):274–85.CrossRefPubMedGoogle Scholar
  108. 108.
    Johnson BF, et al. Vascular endothelial growth factor and immunosuppression in cancer: current knowledge and potential for new therapy. Expert Opin Biol Ther. 2007;7(4):449–60.CrossRefPubMedGoogle Scholar
  109. 109.
    Ciardiello F, Tortora G. Epidermal growth factor receptor (EGFR) as a target in cancer therapy: understanding the role of receptor expression and other molecular determinants that could influence the response to anti-EGFR drugs. Eur J Cancer. 2003;39(10):1348–54.CrossRefPubMedGoogle Scholar
  110. 110.
    Uyttenhove C, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9(10):1269–74.CrossRefPubMedGoogle Scholar
  111. 111.
    Oehler JR, et al. Natural cell-mediated cytotoxicity in rats. II. In vivo augmentation of NK-cell activity. Int J Cancer. 1978;21(2):210–20.CrossRefPubMedGoogle Scholar
  112. 112.
    Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9(11):798–809.PubMedCentralCrossRefPubMedGoogle Scholar
  113. 113.
    Ho HH, Ivashkiv LB. Role of STAT3 in type I interferon responses. Negative regulation of STAT1-dependent inflammatory gene activation. J Biol Chem. 2006;281(20):14111–8.CrossRefPubMedGoogle Scholar
  114. 114.
    Schaefer C, et al. Characteristics of CD4+CD25+ regulatory T cells in the peripheral circulation of patients with head and neck cancer. Br J Cancer. 2005;92(5):913–20.PubMedCentralCrossRefPubMedGoogle Scholar
  115. 115.
    Wansom D, et al. Correlation of cellular immunity with human papillomavirus 16 status and outcome in patients with advanced oropharyngeal cancer. Arch Otolaryngol Head Neck Surg. 2010;136(12):1267–73.PubMedCentralCrossRefPubMedGoogle Scholar
  116. 116.
    Green VL, et al. Increased prevalence of tumour infiltrating immune cells in oropharyngeal tumours in comparison to other subsites: relationship to peripheral immunity. Cancer Immunol Immunother. 2013;62(5):863–73.CrossRefPubMedGoogle Scholar
  117. 117.
    Chikamatsu K, et al. Immunosuppressive activity of CD14+ HLA-DR- cells in squamous cell carcinoma of the head and neck. Cancer Sci. 2012;103(6):976–83.CrossRefPubMedGoogle Scholar
  118. 118.
    Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol. 2009;182(8):4499–506.PubMedCentralCrossRefPubMedGoogle Scholar
  119. 119.
    Grizzle WE, et al. Age-related increase of tumor susceptibility is associated with myeloid-derived suppressor cell mediated suppression of T cell cytotoxicity in recombinant inbred BXD12 mice. Mech Ageing Dev. 2007;128(11–12):672–80.CrossRefPubMedGoogle Scholar
  120. 120.
    Costa NL, et al. Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma. Oral Oncol. 2013;49(3):216–23.CrossRefPubMedGoogle Scholar
  121. 121.
    Fujii N, et al. Cancer-associated fibroblasts and CD163-positive macrophages in oral squamous cell carcinoma: their clinicopathological and prognostic significance. J Oral Pathol Med. 2012;41(6):444–51.CrossRefPubMedGoogle Scholar
  122. 122.
    Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014–22.PubMedCentralCrossRefPubMedGoogle Scholar
  123. 123.
    Gajewski TF. The next hurdle in Cancer immunotherapy: overcoming the non-T-cell-inflamed tumor microenvironment. Semin Oncol. 2015;42(4):663–71.PubMedCentralCrossRefPubMedGoogle Scholar
  124. 124.
    Hanna GJ, et al. Defining an inflamed tumor immunophenotype in recurrent, metastatic squamous cell carcinoma of the head and neck. Oral Oncol. 2017;67:61–9.CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Ferris RL, Jaffee EM, Ferrone S. Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape. J Clin Oncol. 2010;28(28):4390–9.PubMedCentralCrossRefPubMedGoogle Scholar
  126. 126.
    Lee SC, et al. Natural killer (NK): dendritic cell (DC) cross talk induced by therapeutic monoclonal antibody triggers tumor antigen-specific T cell immunity. Immunol Res. 2011;50(2–3):248–54.PubMedCentralCrossRefPubMedGoogle Scholar
  127. 127.
    Kondadasula SV, et al. Colocalization of the IL-12 receptor and FcgammaRIIIa to natural killer cell lipid rafts leads to activation of ERK and enhanced production of interferon-gamma. Blood. 2008;111(8):4173–83.PubMedCentralCrossRefPubMedGoogle Scholar
  128. 128.
    Srivastava RM, et al. Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients. Clin Cancer Res. 2013;19(7):1858–72.PubMedCentralCrossRefPubMedGoogle Scholar
  129. 129.
    Trivedi S, Jie HB, Ferris RL. Tumor antigen-specific monoclonal antibodies and induction of T-cell immunity. Semin Oncol. 2014;41(5):678–84.PubMedCentralCrossRefPubMedGoogle Scholar
  130. 130.
    Jie HB, et al. CTLA-4(+) regulatory T cells increased in Cetuximab-treated head and neck Cancer patients suppress NK cell cytotoxicity and correlate with poor prognosis. Cancer Res. 2015;75(11):2200–10.PubMedCentralCrossRefPubMedGoogle Scholar
  131. 131.
    Chow LQ, et al. Antitumor activity of Pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol. 2016;34:3838.CrossRefPubMedGoogle Scholar
  132. 132.
    Oehler JR, et al. Natural cell-mediated cytotoxicity in rats. I. Tissue and strain distribution, and demonstration of a membrane receptor for the Fc portion of IgG. Int J Cancer. 1978;21(2):204–9.CrossRefPubMedGoogle Scholar
  133. 133.
    Segal NH, Antonia SJ, Brahmer JR, Maio M, Blake-Haskins A, Li X, et al. Safety and efficacy of MEDI4736, an anti-PD-L1 antibody, in patients from a squamous cell carcinoma of the head and neck (SCCHN) expansion cohort. J Clin Oncol. 33(15):3011.Google Scholar
  134. 134.
    Kesselheim AS, Ferris TG, Studdert DM. Will physician-level measures of clinical performance be used in medical malpractice litigation? JAMA. 2006;295(15):1831–4.CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Morris JC, et al. The uniform data set (UDS): clinical and cognitive variables and descriptive data from Alzheimer disease centers. Alzheimer Dis Assoc Disord. 2006;20(4):210–6.CrossRefPubMedGoogle Scholar
  136. 136.
    Nagata Y, et al. Clinical significance of HLA class I alleles on postoperative prognosis of lung cancer patients in Japan. Lung Cancer. 2009;65(1):91–7.CrossRefPubMedGoogle Scholar
  137. 137.
    Albers AE, et al. Alterations in the T-cell receptor variable beta gene-restricted profile of CD8+ T lymphocytes in the peripheral circulation of patients with squamous cell carcinoma of the head and neck. Clin Cancer Res. 2006;12(8):2394–403.CrossRefPubMedGoogle Scholar
  138. 138.
    Gildener-Leapman N, Lee J, Ferris RL. Tailored immunotherapy for HPV positive head and neck squamous cell cancer. Oral Oncol. 2014;50(9):780–4.CrossRefPubMedGoogle Scholar
  139. 139.
    DeRosier LC, et al. Combination treatment with TRA-8 anti death receptor 5 antibody and CPT-11 induces tumor regression in an orthotopic model of pancreatic cancer. Clin Cancer Res. 2007;13(18 Pt 2):5535s–43s.PubMedCentralCrossRefPubMedGoogle Scholar
  140. 140.
    Curran MA, et al. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107(9):4275–80.PubMedCentralCrossRefPubMedGoogle Scholar
  141. 141.
    Costache M, et al. Ciliary body melanoma - a particularly rare type of ocular tumor. Case report and general considerations. Maedica (Buchar). 2013;8(4):360–4.Google Scholar
  142. 142.
    Chan AT, Teo PM, Johnson PJ. Nasopharyngeal carcinoma. Ann Oncol. 2002;13(7):1007–15.CrossRefPubMedGoogle Scholar
  143. 143.
    Li L, et al. Targeting poly(ADP-ribose) polymerase and the c-Myb-regulated DNA damage response pathway in castration-resistant prostate cancer. Sci Signal. 2014;7(326):ra47.PubMedCentralCrossRefPubMedGoogle Scholar
  144. 144.
    Chatrchyan S, et al. Observation of the associated production of a single top quark and a W boson in pp collisions at sqrt[s] = 8 TeV. Phys Rev Lett. 2014;112(23):231802.CrossRefPubMedGoogle Scholar
  145. 145.
    Chatrchyan S, et al. Measurement of inclusive W and Z boson production cross sections in pp collisions at sqrt[s] = 8 TeV. Phys Rev Lett. 2014;112(19):191802.CrossRefPubMedGoogle Scholar
  146. 146.
    Chatrchyan S, et al. Search for flavor-changing neutral currents in top-quark decays t --> Zq in pp collisions at sqrt[s] = 8 TeV. Phys Rev Lett. 2014;112(17):171802.CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Chatrchyan S, et al. Search for top squark and Higgsino production using diphoton Higgs boson decays. Phys Rev Lett. 2014;112(16):161802.CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Thompson RF, Maity A. Radiotherapy and the tumor microenvironment: mutual influence and clinical implications. Adv Exp Med Biol. 2014;772:147–65.CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Hodge JW, et al. The tipping point for combination therapy: cancer vaccines with radiation, chemotherapy, or targeted small molecule inhibitors. Semin Oncol. 2012;39(3):323–39.PubMedCentralCrossRefPubMedGoogle Scholar
  150. 150.
    Hodge JW, et al. Attacking malignant cells that survive therapy: exploiting immunogenic modulation. Oncoimmunology. 2013;2(12):e26937.PubMedCentralCrossRefPubMedGoogle Scholar
  151. 151.
    Martins I, et al. Surface-exposed calreticulin in the interaction between dying cells and phagocytes. Ann N Y Acad Sci. 2010;1209:77–82.CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Hodge JW, et al. Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. Int J Cancer. 2013;133(3):624–36.PubMedCentralCrossRefPubMedGoogle Scholar
  153. 153.
    Gameiro SR, et al. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget. 2014;5(2):403–16.CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Folch E, et al. Adequacy of lymph node transbronchial needle aspirates using convex probe endobronchial ultrasound for multiple tumor genotyping techniques in non-small-cell lung cancer. J Thorac Oncol. 2013;8(11):1438–44.PubMedCentralCrossRefPubMedGoogle Scholar
  155. 155.
    Emens LA, Middleton G. The interplay of immunotherapy and chemotherapy: harnessing potential synergies. Cancer Immunol Res. 2015;3(5):436–43.PubMedCentralCrossRefPubMedGoogle Scholar
  156. 156.
    Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. 2013;105(4):256–65.PubMedCentralCrossRefPubMedGoogle Scholar
  157. 157.
    Demaria S, et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005;11(2 Pt 1):728–34.PubMedPubMedCentralGoogle Scholar
  158. 158.
    Langer CJ, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497–508.CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Rizvi NA, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung Cancer. J Clin Oncol. 2016;34(25):2969–79.PubMedCentralCrossRefPubMedGoogle Scholar
  160. 160.
    Reck M, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung Cancer. N Engl J Med. 2016;375(19):1823–33.CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Borghaei H, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung Cancer. N Engl J Med. 2015;373(17):1627–39.PubMedCentralCrossRefPubMedGoogle Scholar
  162. 162.
    Pego-Fernandes PM, et al. Double valve replacement due to dysfunction secondary to carcinoid tumor. Arq Bras Cardiol. 2013;100(3):e32–4.CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Ferris RL, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856–67.PubMedCentralCrossRefPubMedGoogle Scholar
  164. 164.
    Das R, et al. Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. J Immunol. 2015;194(3):950–9.CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Larkin J, et al. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34.PubMedCentralCrossRefPubMedGoogle Scholar
  166. 166.
    Bullhe SH. Kalāma Buḷḷe Shāha1990, Paṭiālā: Bhāshā Wibhāga, Pañjāba 12, 187 p.Google Scholar
  167. 167.
    Guo Z, et al. PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer. PLoS One. 2014;9(2):e89350.PubMedCentralCrossRefPubMedGoogle Scholar
  168. 168.
    Camirand G, et al. CD45 ligation expands Tregs by promoting interactions with DCs. J Clin Invest. 2014;124(10):4603–13.PubMedCentralCrossRefPubMedGoogle Scholar
  169. 169.
    Hodi FS, et al. Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma. Cancer Immunol Res. 2014;2(7):632–642.Google Scholar
  170. 170.
    Holmgaard RB, et al. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. 2013;210(7):1389–402.PubMedCentralCrossRefPubMedGoogle Scholar
  171. 171.
    Cai J, et al. ATP hydrolysis catalyzed by human replication factor C requires participation of multiple subunits. Proc Natl Acad Sci U S A. 1998;95(20):11607–12.PubMedCentralCrossRefPubMedGoogle Scholar
  172. 172.
    Kohrt HE, et al. Targeting CD137 enhances the efficacy of cetuximab. J Clin Invest. 2014;124(6):2668–82.PubMedCentralCrossRefPubMedGoogle Scholar
  173. 173.
    Chatrchyan S, et al. Probing color coherence effects in pp collisions at [formula: see text]. Eur Phys J C Part Fields. 2014;74(6):2901.PubMedCentralCrossRefPubMedGoogle Scholar
  174. 174.
    Zaretsky JM, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375(9):819–29.PubMedCentralCrossRefPubMedGoogle Scholar
  175. 175.
    Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231–5.CrossRefGoogle Scholar
  176. 176.
    Peng W, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 2016;6(2):202–16.CrossRefPubMedGoogle Scholar
  177. 177.
    Boni A, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70(13):5213–9.CrossRefPubMedGoogle Scholar
  178. 178.
    Frederick DT, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19(5):1225–31.PubMedCentralCrossRefPubMedGoogle Scholar
  179. 179.
    Ribas A, et al. Association of Pembrolizumab with Tumor Response and Survival among Patients with Advanced Melanoma. JAMA. 2016;315(15):1600–9.CrossRefPubMedGoogle Scholar
  180. 180.
    Harlin H, et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009;69(7):3077–85.CrossRefPubMedGoogle Scholar
  181. 181.
    Sweis RF, et al. Molecular drivers of the non-T-cell-inflamed tumor microenvironment in urothelial bladder Cancer. Cancer Immunol Res. 2016;4(7):563–8.PubMedCentralCrossRefPubMedGoogle Scholar
  182. 182.
    Keck MK, et al. Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. Clin Cancer Res. 2015;21(4):870–81.CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Sharma P, et al. Primary, adaptive, and acquired resistance to Cancer immunotherapy. Cell. 2017;168(4):707–23.PubMedCentralCrossRefPubMedGoogle Scholar
  184. 184.
    Topalian SL, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.PubMedCentralCrossRefPubMedGoogle Scholar
  185. 185.
    Gillison ML, Blumenschein G, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab (nivo) vs investigator’s choice (IC) for recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): Checkmate 141. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research. New Orleans\Philadelphia: AACR; Cancer Res; 2016. 2016;76(14 Suppl):Abstract nr CT099.Google Scholar
  186. 186.
    Seiwert TY, Burtness B, Weiss J, Gluck I, Elder JP, Pai SI, et al. A phase Ib study of MK-3475 in patients with human papillomavirus (HPV)-associated and non-HPV-associated head and neck (H/N) cancer. J Clin Oncol. 2014, May 20;32(15 Suppl):6011.Google Scholar
  187. 187.
    Aguiar PN Jr, et al. The role of PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: a network meta-analysis. Immunotherapy. 2016;8(4):479–88.CrossRefPubMedGoogle Scholar
  188. 188.
    Tumeh PC, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71.PubMedCentralCrossRefPubMedGoogle Scholar
  189. 189.
    Johnson DB, et al. Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. Nat Commun. 2016;7:10582.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of OtolaryngologyUniversity of PittsburghPittsburghUSA
  2. 2.UPMC Hillman Cancer CenterPittsburghUSA
  3. 3.Department of ImmunologyUniversity of PittsburghPittsburghUSA
  4. 4.Hillman Cancer Center Research PavilionPittsburghUSA

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