Immune checkpoint pathways in immunotherapy for head and neck squamous cell carcinoma

Abstract

With the understanding of the complex interaction between the tumour microenvironment and immunotherapy, there is increasing interest in the role of immune regulators in the treatment of head and neck squamous cell carcinoma (HNSCC). Activation of T cells and immune checkpoint molecules is important for the immune response to cancers. Immune checkpoint molecules include cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), T-cell immunoglobulin mucin protein 3 (TIM-3), lymphocyte activation gene 3 (LAG-3), T cell immunoglobin and immunoreceptor tyrosine-based inhibitory motif (TIGIT), glucocorticoid-induced tumour necrosis factor receptor (GITR) and V-domain Ig suppressor of T cell activation (VISTA). Many clinical trials using checkpoint inhibitors, as both monotherapies and combination therapies, have been initiated targeting these immune checkpoint molecules. This review summarizes the functional mechanism and use of various immune checkpoint molecules in HNSCC, including monotherapies and combination therapies, and provides better treatment options for patients with HNSCC.

References

[1] Bray F, . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68: 394-424.

[2] Pulte D, Brenner H. Changes in survival in head and neck cancers in the late 20th and early 21st century: a period analysis. Oncologist, 2010, 15: 994-1001.

[3] Kuss I, Hathaway B, Ferris R, Gooding W, Whiteside T. 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: 3755-3762.

[4] Nordfors C, . CD8+ and CD4+ tumour infiltrating lymphocytes in relation to human papillomavirus status and clinical outcome in tonsillar and base of tongue squamous cell carcinoma. Eur. J. Cancer, 2013, 49: 2522-2530.

[5] Fridman W, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer, 2010, 12: 298-306.

[6] Lee MH, . Interleukin 17 and peripheral IL-17-expressing T cells are negatively correlated with the overall survival of head and neck cancer patients. Oncotarget, 2019, 9: 9825-9837.

[7] López-Albaitero A, . 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: 3402-3409.

[8] Mizukami Y, . 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: 1462-1467.

[9] Ferris RL. Immunology and Immunotherapy of Head and Neck Cancer. J. Clin. Oncol., 2015, 33: 3293-3304.

[10] Ferris RL, Whiteside TL, Ferrone S. Immune escape associated with functional defects in antigen-processing machinery in head and neck cancer. Clin. Cancer Res., 2016, 12: 3890-3895.

[11] Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat. Rev. Immunol., 2008, 8: 467-477.

[12] Wang XB, . CTLA4 is expressed on mature dendritic cells derived from human monocytes and influences their maturation and antigen presentation. BMC immunol., 2011, 12: 21.

[13] Jie HB, . 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: 2200-2210.

[14] Sullivan TJ, . Lack of a role for transforming growth factor-beta in cytotoxic T lymphocyte antigen-4-mediated inhibition of T cell activation. Proc. Natl Acad. Sci. USA, 2001, 98: 2587-2592.

[15] Wing JB, Ise W, Kurosaki T, Sakaguchi S. Regulatory T cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4. Immunity, 2014, 41: 1013-1025.

[16] Qureshi OS, . Constitutive clathrin-mediated endocytosis of CTLA-4 persists during T cell activation. J. Biol. Chem., 2012, 287: 9429-9440.

[17] De Vicente JC, . PD-L1 expression in tumor cells is an independent unfavorable prognostic factor in oral squamous cell carcinoma. Cancer Epidemiol. Biomark. Prev., 2019, 28: 546-554.

[18] Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol. Cancer Ther., 2015, 14: 847-856.

[19] Hino R, . Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer, 2010, 116: 1757-1766.

[20] Wang A, . The prognostic value of PD-L1 expression for non-small cell lung cancer patients: a meta-analysis. Eur. J. Surg. Oncol., 2015, 41: 450-456.

[21] Zandberg DP, . The role of the PD-L1:PD-1 pathway in squamous cell carcinoma of the head and neck. Oral Oncol., 2014, 50: 627-632.

[22] Lyford-Pike S, . 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: 1733-1741.

[23] Wang W, . PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells. Int. Immunol., 2009, 21: 1065-1077.

[24] Freeman GJ, . 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: 1027-1034.

[25] Monney L, . Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature, 2002, 415: 536-541.

[26] Anderson AC, . Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science, 2007, 318: 1141-1143.

[27] Zhou Q, . Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood, 2011, 117: 4501-4510.

[28] Golden-Mason L, . Galectin-9: Diverse roles in hepatic immune homeostasis and inflammation. Hepatology, 2017, 66: 271-279.

[29] Ngiow SF, . Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors. Cancer Res., 2011, 71: 3540-3551.

[30] Farren MR, . Systemic immune activity predicts overall survival in treatment-naïve patients with metastatic pancreatic cancer. Clin. Cancer Res., 2016, 22: 2565-2574.

[31] Zheng H, . Distinct role of Tim-3 in systemic lupus erythematosus and clear cell renal cell carcinoma. Int J. Clin. Exp. Med., 2015, 8: 7029-7038.

[32] Liu JF, . T-cell immunoglobulin mucin 3 blockade drives an antitumor immune response in head and neck cancer. Mol. Oncol., 2017, 11: 235-247.

[33] Finn O.J.. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Annals of Oncology, 2012, 23: viii6-viii9.

[34] Frisancho-Kiss S, . Gonadectomy of male BALB/c mice increases Tim-3(+) alternatively activated M2 macrophages, Tim-3(+) T cells, Th2 cells and Treg in the heart during acute coxsackievirus-induced myocarditis. Brain Behav. Immun., 2009, 23: 649-657.

[35] Triebel F, . LAG-3, a novel lymphocyte activation gene closely related to CD4. J. Exp. Med., 1990, 171: 1393-1405.

[36] Huard B, . Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes. Eur. J. Immunol., 1994, 24: 3216-3221.

[37] Workman CJ, Vignali DA. The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells. Eur. J. Immunol., 2003, 33: 970-979.

[38] Huang CT, . Role of LAG-3 in regulatory T cells. Immunity, 2004, 21: 503-513.

[39] Woo SR, . Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res., 2012, 72: 917-927.

[40] Huard B, . CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur. J. Immunol., 1995, 25: 2718-2721.

[41] Xu F, . LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res., 2014, 74: 3418-3428.

[42] Matsuzaki J, . Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc. Natl Acad. Sci. USA, 2010, 107: 7875-7880.

[43] Grosso JF, . LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J. Clin. Invest., 2007, 117: 3383-3392.

[44] Jie HB, . Intratumoral regulatory T cells upregulate immunosuppressive molecules in head and neck cancer patients. Br. J. Cancer, 2013, 109: 2629-2635.

[45] Wang J, . Fibrinogen-like Protein 1 is a major immune inhibitory ligand of LAG-3. Cell, 2019, 176: 334-347.

[46] Demchev V, . Targeted deletion of fibrinogen like protein 1 reveals a novel role in energy substrate utilization. PLoS One, 2013, 8

[47] Yu X, . The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat. Immunol., 2009, 10: 48-57.

[48] Fuchs A, Colonna M. The role of NK cell recognition of nectin and nectin-like proteins in tumor immunosurveillance. Semin Cancer Biol., 2006, 16: 359-366.

[49] Lozano E, Dominguez-Villar M, Kuchroo V, Hafler DA. The TIGIT/CD226 axis regulates human T cell function. J. Immunol., 2012, 188: 3869-3875.

[50] Stephens GL, . Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J. Immunol., 2004, 173: 5008-5020.

[51] Schaer DA, . GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability. Cancer Immunol. Res., 2013, 1: 320-331.

[52] Esparza EM, Arch RH. Glucocorticoid-induced TNF receptor functions as a costimulatory receptor that promotes survival in early phases of T cell activation. J. Immunol., 2015, 174: 7869-7874.

[53] Shimizu J, . Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat. Immunol., 2002, 3: 135-142.

[54] Le Mercier I, . VISTA Regulates the development of protective antitumor immunity. Cancer Res., 2014, 74: 1933-1944.

[55] Wang L, . VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J. Exp. Med., 2011, 208: 577-592.

[56] Liu J, . Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc. Natl Acad. Sci. USA, 2015, 112: 6682-6687.

[57] Wang J, . VSIG-3 as a ligand of VISTA inhibits human T-cell function. Immunology, 2019, 156: 74-85.

[58] Harada H, Suzu S, Hayashi Y, Okada S. BT-IgSF, a novel immunoglobulin superfamily protein, functions as a cell adhesion molecule. J. Cell Physiol., 2015, 204: 919-926.

[59] Topalian SL, . Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med., 2012, 366: 2443-2454.

[60] Balar AV, Weber JS. PD-1 and PD-L1 antibodies in cancer: current status and future directions. Cancer Immunol. Immunother., 2017, 66: 551-564.

[61] Kaidar-Person O, Gil Z, Billan S. Precision therapy of head and neck squamous cell carcinoma. J. Dent. Res., 2018, 40: 13-16.

[62] Ferris RL, . Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N. Engl. J. Med., 2016, 375: 1856-1867.

[63] Harrington KJ, . Nivolumab versus standard, single-agent therapy of investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial. Lancet Oncol., 2017, 18: 1104-1115.

[64] Seiwert TY, . 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., 2017, 17: 956-965.

[65] Burtness B, . Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet, 2019, 394: 1915-1928.

[66] Festino L, . Cancer treatment with anti-PD-1/PD-L1 agents: Is PD-L1 expression a biomarker for patient selection?. Drugs, 2016, 6: 925-945.

[67] Chow LQ, . 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: 3838-3845.

[68] Zandberg DP, . Durvalumab for recurrent or metastatic head and neck squamous cell carcinoma: Results from a single-arm, phase II study in patients with ≥25% tumour cell PD-L1 expression who have progressed on platinum-based chemotherapy. Eur. J. Cancer, 2018, 107: 142-152.

[69] Taube JM, . Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res, 2014, 20: 5064-5074.

[70] Yearley JH, . PD-L2 expression in human tumors: relevance to anti-PD-1 therapy in cancer. Clin. Cancer Res, 2017, 23: 3158-3167.

[71] Zhang J, . Co-expression of PD-1 and PD-L1 predicts poor outcome in nasopharyngeal carcinoma. Med. Oncol., 2015, 32

[72] Lee VH, . Correlation of PD-L1 expression of tumor cells with survival outcomes after radical intensity-modulated radiation therapy for non-metastatic nasopharyngeal carcinoma. PLoS One., 2016, 11

[73] Blank CU. Therapeutic use of anti-CTLA-4 antibodies. Int. Immunol., 2015, 27: 3-10.

[74] Camacho LH, . Phase I/II trial of tremelimumab in patients with metastatic melanoma. J. Clin. Oncol., 2009, 27: 1075-1081.

[75] Hamid O, . A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J. Transl. Med., 2011, 9

[76] Reck M, . Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann. Oncol., 2013, 24: 75-83.

[77] Lynch TJ, . Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J. Clin. Oncol., 2012, 30: 2046-2054.

[78] Tran B, . Dose escalation results from a first-in-human, phase 1 study of glucocorticoid-induced TNF receptor-related protein agonist AMG 228 in patients with advanced solid tumors. J. Immunother. Cancer, 2018, 6: 93.

[79] Kim JE, . Combination therapy with anti-PD-1, Anti-TIM-3, and focal radiation results in regression of murine gliomas. Clin. Cancer Res., 2017, 23: 124-136.

[80] Ascierto PA, . Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti–PD-1/PD-L1 therapy. J. Clin. Oncol., 2017, 35: 9520.

[81] Koyama S, . Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat. Commun., 2016, 7

[82] Schwab KS, . Successful treatment of refractory squamous cell cancer of the head and neck with nivolumab and ipilimumab. Case Rep. Oncol., 2018, 11: 17-20.

[83] Shevach EM, Stephens GL. The GITR-GITRL interaction: co-stimulation or contrasuppression of regulatory activity?. Nat. Rev. Immunol., 2006, 6: 613-618.

[84] Siu LL, . Preliminary results of a phase I/IIa study of BMS-986156 (glucocorticoid-induced tumor necrosis factor receptor–related gene [GITR] agonist), alone and in combination with nivolumab in pts with advanced solid tumors. J. Clin. Oncol., 2017, 35: 104-104.

[85] Trommer M, . Abscopal effects in radio-immunotherapy-response analysis of metastatic cancer patients with progressive disease under anti-PD-1 immune checkpoint inhibition. Front Pharmacol., 2019, 10: 511.

[86] Ko EC, Formenti SC. Radiation therapy to enhance tumor immunotherapy: a novel application for an established modality. Int. J. Radiat. Biol., 2019, 95: 936-939.

[87] Zappasodi R, Merghoub T, Wolchok JD. Emerging concepts for immune checkpoint blockade-based combination therapies. Cancer Cell., 2018, 34: 581-598.

[88] Cruz E, Kayser V. Monoclonal antibody therapy of solid tumors: clinical limitations and novel strategies to enhance treatment efficacy. Biologics, 2019, 13: 33-51.

[89] Qiao M, Jiang T, Ren S, Zhou C. Combination strategies on the basis of immune checkpoint inhibitors in non-small-cell lung cancer: where do we stand?. Clin. Lung Cancer, 2018, 19: 1-11.

[90] Garassino MC, Torri V, Colombo MP, Sica A. Choosing the best chemotherapy agent to boost immune checkpoint inhibition activity. Cancer Res., 2018, 78: 5729-5730.

[91] Morris V, Kopetz S. BRAF inhibitors in clinical oncology. F1000Prime Rep., 2013, 5: 11.

[92] Sullivan RJ, . Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat. Med., 2019, 25: 929-935.

[93] Amaria RN, . Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol., 2018, 19: 181-193.

[94] Kuusk T, . Antiangiogenic therapy combined with immune checkpoint blockade in renal cancer. Angiogenesis, 2017, 20: 205-215.

[95] Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N. Engl. J. Med., 2017, 376: 354-366.

[96] Caruso C. Checkpoint Inhibitor-TKI Combos Effective in RCC. Cancer Discov, 2019, 9: 460.

[97] De Henau O, . Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature, 2016, 539: 443-447.

[98] Prins RM, . Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients. J. Immunother., 2013, 36: 152-157.

[99] Kos S, . Intradermal DNA vaccination combined with dual CTLA-4 and PD-1 blockade provides robust tumor immunity in murine melanoma. PloS One, 2019, 14

[100] Cruickshank B, . Dying to be noticed: epigenetic regulation of immunogenic cell death for cancer immunotherapy. Front Immunol., 2018, 9: 654.

[101] Ng HY, . Chemotherapeutic treatments increase PD-L1 expression in esophageal squamous cell carcinoma through EGFR/ERK activation. Transl. Oncol., 2018, 11: 1323-1333.