Inflammation and Head and Neck Squamous Cell Carcinoma

  • Paul E. Clavijo
  • Clint T. Allen
  • Nicole C. Schmitt
  • Carter Van WaesEmail author
Part of the Current Cancer Research book series (CUCR)


Inflammation is a process that is involved in several stages of development and malignant progression of head and neck squamous cell carcinoma. Tobacco and alcohol, human papillomaviruses (HPV), or Epstein-Barr viruses (EBV) can initiate and establish chronic inflammation through a variety of mechanisms. Genomic alterations or viral oncoproteins that induce signaling via phosphatidylinositol 3-kinase (PI3K) and transcription factor nuclear factor-kappaB (NF-κB) regulate numerous genes that promote survival of cancer cells, while they induce inflammatory myeloid-derived suppressor cell (MDSC) and T regulatory (Treg) cell responses that interfere with effector T-cell immunity. Molecular therapies targeting signaling in cancer cells and these deleterious inflammatory cells are being combined with new PD-L1/PD-1 and CTLA-4 immune checkpoint inhibitors to explore better ways to harness the immune system in control of cancer.


Inflammation Cytokines Tumor necrosis factor PI3K NF-kappaB T regulatory cells Myeloid-derived suppressor cells 


  1. 1.
    Gasparoto TH, et al. Inflammatory events during murine squamous cell carcinoma development. J Inflamm (Lond). 2012;9(1):46.CrossRefGoogle Scholar
  2. 2.
    Choudhari SK, et al. Oxidative and antioxidative mechanisms in oral cancer and precancer: a review. Oral Oncol. 2014;50(1):10–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Hecht SS. Lung carcinogenesis by tobacco smoke. Int J Cancer. 2012;131(12):2724–32.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    West KA, et al. Tobacco carcinogen-induced cellular transformation increases Akt activation in vitro and in vivo. Chest. 2004;125(5 Suppl):101S–2S.CrossRefPubMedGoogle Scholar
  5. 5.
    Tsurutani J, et al. Tobacco components stimulate Akt-dependent proliferation and NFkappaB-dependent survival in lung cancer cells. Carcinogenesis. 2005;26(7):1182–95.CrossRefPubMedGoogle Scholar
  6. 6.
    Dennis PA, et al. The biology of tobacco and nicotine: bench to bedside. Cancer Epidemiol Biomark Prev. 2005;14(4):764–7.CrossRefGoogle Scholar
  7. 7.
    Miyamoto S. Nuclear initiated NF-kappaB signaling: NEMO and ATM take center stage. Cell Res. 2011;21(1):116–30.CrossRefPubMedGoogle Scholar
  8. 8.
    Zu Y, et al. Lipopolysaccharide-induced toll-like receptor 4 signaling in esophageal squamous cell carcinoma promotes tumor proliferation and regulates inflammatory cytokines expression. Dis Esophagus. 2017;30(2):1–8.PubMedGoogle Scholar
  9. 9.
    Farnebo L, et al. Targeting toll-like receptor 2 inhibits growth of head and neck squamous cell carcinoma. Oncotarget. 2015;6(12):9897–907.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Van Waes C. Nuclear factor-kappaB in development, prevention, and therapy of cancer. Clin Cancer Res. 2007;13(4):1076–82.CrossRefPubMedGoogle Scholar
  11. 11.
    Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82.CrossRefGoogle Scholar
  12. 12.
    Hutti JE, et al. Oncogenic PI3K mutations lead to NF-kappaB-dependent cytokine expression following growth factor deprivation. Cancer Res. 2012;72(13):3260–9.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Yang X, et al. DeltaNp63 versatilely regulates a broad NF-kappaB gene program and promotes squamous epithelial proliferation, migration, and inflammation. Cancer Res. 2011;71(10):3688–700.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lee TL, et al. A signal network involving coactivated NF-kappaB and STAT3 and altered p53 modulates BAX/BCL-XL expression and promotes cell survival of head and neck squamous cell carcinomas. Int J Cancer. 2008;122(9):1987–98.CrossRefPubMedGoogle Scholar
  15. 15.
    Duan J, et al. Nuclear factor-kappaB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101. Mol Cancer Ther. 2007;6(1):37–50.CrossRefPubMedGoogle Scholar
  16. 16.
    Duffey DC, et al. Expression of a dominant-negative mutant inhibitor-kappaBalpha of nuclear factor-kappaB in human head and neck squamous cell carcinoma inhibits survival, proinflammatory cytokine expression, and tumor growth in vivo. Cancer Res. 1999;59(14):3468–74.PubMedGoogle Scholar
  17. 17.
    Bancroft CC, et al. Coexpression of proangiogenic factors IL-8 and VEGF by human head and neck squamous cell carcinoma involves coactivation by MEK-MAPK and IKK-NF-kappaB signal pathways. Clin Cancer Res. 2001;7(2):435–42.PubMedGoogle Scholar
  18. 18.
    Loukinova E, et al. Expression of proangiogenic chemokine Gro 1 in low and high metastatic variants of pam murine squamous cell carcinoma is differentially regulated by IL-1alpha, EGF and TGF-beta1 through NF-kappaB dependent and independent mechanisms. Int J Cancer. 2001;94(5):637–44.CrossRefPubMedGoogle Scholar
  19. 19.
    Loukinova E, et al. Growth regulated oncogene-alpha expression by murine squamous cell carcinoma promotes tumor growth, metastasis, leukocyte infiltration and angiogenesis by a host CXC receptor-2 dependent mechanism. Oncogene. 2000;19(31):3477–86.CrossRefPubMedGoogle Scholar
  20. 20.
    Young MR, et al. Human squamous cell carcinomas of the head and neck chemoattract immune suppressive CD34(+) progenitor cells. Hum Immunol. 2001;62(4):332–41.CrossRefPubMedGoogle Scholar
  21. 21.
    Pak AS, et al. Mechanisms of immune suppression in patients with head and neck cancer: presence of CD34(+) cells which suppress immune functions within cancers that secrete granulocyte-macrophage colony-stimulating factor. Clin Cancer Res. 1995;1(1):95–103.PubMedGoogle Scholar
  22. 22.
    Sawanobori Y, et al. Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood. 2008;111(12):5457–66.CrossRefPubMedGoogle Scholar
  23. 23.
    Youn JI, et al. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol. 2008;181(8):5791–802.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Sakaguchi S, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155(3):1151–64.PubMedGoogle Scholar
  25. 25.
    Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol. 2003;3(3):253–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Beyer M, Schultze JL. Regulatory T cells in cancer. Blood. 2006;108(3):804–11.CrossRefPubMedGoogle Scholar
  27. 27.
    Tartour E, et al. Serum soluble interleukin-2 receptor concentrations as an independent prognostic marker in head and neck cancer. Lancet. 2001;357(9264):1263–4.CrossRefPubMedGoogle Scholar
  28. 28.
    Kumar V, et al. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 2016;37(3):208–20.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Rodriguez PC, et al. Regulation of T cell receptor CD3zeta chain expression by L-arginine. J Biol Chem. 2002;277(24):21123–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Mazzoni A, et al. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol. 2002;168(2):689–95.CrossRefPubMedGoogle Scholar
  31. 31.
    Schindler H, Bogdan C. NO as a signaling molecule: effects on kinases. Int Immunopharmacol. 2001;1(8):1443–55.CrossRefPubMedGoogle Scholar
  32. 32.
    Lee GK, et al. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology. 2002;107(4):452–60.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Huang B, et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res. 2006;66(2):1123–31.CrossRefPubMedGoogle Scholar
  34. 34.
    Huang B, et al. CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Lett. 2007;252(1):86–92.CrossRefGoogle Scholar
  35. 35.
    Youn JI, et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat Immunol. 2013;14(3):211–20.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    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
  37. 37.
    Chen WC, et al. Inflammation-induced myeloid-derived suppressor cells associated with squamous cell carcinoma of the head and neck. Head Neck. 2017;39(2):347–55.CrossRefPubMedGoogle Scholar
  38. 38.
    Corzo CA, et al. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010;207(11):2439–53.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Clavijo PE, et al. Resistance to CTLA-4 checkpoint inhibition reversed through selective elimination of granulocytic myeloid cells. Oncotarget. 2017;8(34):55804–20.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Chen Z, et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res. 1999;5(6):1369–79.PubMedGoogle Scholar
  41. 41.
    Califano JA, et al. Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21(1):30–8.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Weed DT, et al. Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21(1):39–48.CrossRefPubMedGoogle Scholar
  43. 43.
    Davis RJ, et al. Anti-PD-L1 efficacy can be enhanced by inhibition of myeloid-derived suppressor cells with a selective inhibitor of PI3Kdelta/gamma. Cancer Res. 2017;77(10):2607–19.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Ondondo B, et al. Home sweet home: the tumor microenvironment as a haven for regulatory T cells. Front Immunol. 2013;4:197.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Chaudhary B, Elkord E. Regulatory T cells in the tumor microenvironment and Cancer progression: role and therapeutic targeting. Vaccines (Basel). 2016;4(3): pii, E28.Google Scholar
  46. 46.
    Chikamatsu K, et al. Relationships between regulatory T cells and CD8+ effector populations in patients with squamous cell carcinoma of the head and neck. Head Neck. 2007;29(2):120–7.CrossRefPubMedGoogle Scholar
  47. 47.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Lau KM, et al. Increase in circulating Foxp3+CD4+CD25(high) regulatory T cells in nasopharyngeal carcinoma patients. Br J Cancer. 2007;96(4):617–22.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Shang B, et al. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep. 2015;5:15179.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Venet F, et al. Human CD4+CD25+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J Immunol. 2006;177(9):6540–7.CrossRefPubMedGoogle Scholar
  52. 52.
    Ali K, et al. Inactivation of PI(3)K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature. 2014;510(7505):407–11.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Wing K, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271–5.CrossRefPubMedGoogle Scholar
  54. 54.
    Parry RV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25(21):9543–53.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Peggs KS, et al. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009;206(8):1717–25.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Tarhini AA, et al. Differing patterns of circulating regulatory T cells and myeloid-derived suppressor cells in metastatic melanoma patients receiving anti-CTLA4 antibody and interferon-alpha or TLR-9 agonist and GM-CSF with peptide vaccination. J Immunother. 2012;35(9):702–10.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Wang W, et al. PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(hi) regulatory T cells. Int Immunol. 2009;21(9):1065–77.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Schuler PJ, et al. Effects of adjuvant chemoradiotherapy on the frequency and function of regulatory T cells in patients with head and neck cancer. Clin Cancer Res. 2013;19(23):6585–96.CrossRefPubMedGoogle Scholar
  59. 59.
    Vander Broek R, et al. The PI3K/Akt/mTOR axis in head and neck cancer: functions, aberrations, cross-talk, and therapies. Oral Dis. 2015;21(7):815–25.CrossRefPubMedGoogle Scholar
  60. 60.
    Taube JM, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4(127):127ra37.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    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.CrossRefPubMedGoogle Scholar
  62. 62.
    Ferris RL, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856–67.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    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.CrossRefPubMedGoogle Scholar
  64. 64.
    Woo SR, Corrales L, Gajewski TF. Innate immune recognition of cancer. Annu Rev Immunol. 2015;33:445–74.CrossRefPubMedGoogle Scholar
  65. 65.
    Corrales L, et al. The host STING pathway at the interface of cancer and immunity. J Clin Invest. 2016;126(7):2404–11.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Moore E, et al. Established T cell-inflamed tumors rejected after adaptive resistance was reversed by combination STING activation and PD-1 pathway blockade. Cancer Immunol Res. 2016;4(12):1061–71.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Gadkaree SK, et al. Induction of tumor regression by intratumoral STING agonists combined with anti-programmed death-L1 blocking antibody in a preclinical squamous cell carcinoma model. Head Neck. 2017;39(6):1086–94.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Paul E. Clavijo
    • 1
  • Clint T. Allen
    • 1
  • Nicole C. Schmitt
    • 1
  • Carter Van Waes
    • 1
    Email author
  1. 1.Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of HealthBethesdaUSA

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