Immune Checkpoints Pathways in Head and Neck Squamous Cell Carcinoma

Florencia Veigas, Yamil D Mahmoud, Joaquin Merlo, Adriana Rinflerch, Gabriel Adrian Rabinovich, María Romina Girotti, Florencia Veigas, Yamil D Mahmoud, Joaquin Merlo, Adriana Rinflerch, Gabriel Adrian Rabinovich, María Romina Girotti

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors usually diagnosed at an advanced stage and characterized by a poor prognosis. The main risk factors associated with its development include tobacco and alcohol consumption and Human Papillomavirus (HPV) infections. The immune system has a significant role in the oncogenesis and evolution of this cancer type. Notably, the immunosuppressive tumor microenvironment triggers immune escape through several mechanisms. The improved understanding of the antitumor immune response in solid tumors and the role of the immune checkpoint molecules and other immune regulators have led to the development of novel therapeutic strategies that revolutionized the clinical management of HNSCC. However, the limited overall response rate to immunotherapy urges identifying predictive biomarkers of response and resistance to treatment. Here, we review the role of the immune system and immune checkpoint pathways in HNSCC, the most relevant clinical findings linked to immunotherapeutic strategies and predictive biomarkers of response and future treatment perspectives.

Keywords: head and neck cancer; immune checkpoint; immune infiltrate; immunotherapy.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Immune checkpoints in head and neck squamous cell carcinoma (HNSCC). The main immune checkpoint pathways involved in HNSCC immune escape are illustrated: PD-1/PD-L1, CTLA-4, TIM-3, LAG-3, and TIGIT. Through different molecular mechanisms and signaling pathways, immune checkpoint molecules promote apoptosis of T cells, inhibit the effector function of T cells, and induce expansion of immunosuppressive MDSCs, M2-like TAMs, and Tregs. A novel soluble immune checkpoint implicated in HNSCC is Gal-1. Gal-1 is expressed by tumor cells triggering immune escape, modulation of tumor endothelium, and metastasis.

References

    1. Laura Q.M., Chow M.D. Head and Neck Cancer. N. Engl. J. Med. 2020;382:60–72. doi: 10.1056/nejmra1715715.
    1. Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. 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. doi: 10.3322/caac.21492.
    1. WHO Globocan 2018 Database. Issued by World Health Organization (WHO) [(accessed on 30 January 2021)]; Available online: .
    1. Mork J., Lie A.K., Glattre E., Clark S., Hallmans G., Jellum E., Koskela P., Møller B., Pukkala E., Schiller J.T., et al. Human Papillomavirus Infection as a Risk Factor for Squamous-Cell Carcinoma of the Head and Neck. J. Natl. Cancer Inst. 2001;344:1125–1131. doi: 10.1056/NEJM200104123441503.
    1. Hashibe M., Brennan P., Benhamou S., Castellsagué X., Chen C., Curado M.P., Dal Maso L., Daudt A.W., Fabianova E., Franceschi V.W.-F.S., et al. Alcohol Drinking in Never Users of Tobacco, Cigarette Smoking in Never Drinkers, and the Risk of Head and Neck Cancer: Pooled Analysis in the International Head and Neck Cancer Epidemiology Consortium. J. N. Inst. 2007;99:777–789. doi: 10.1093/jnci/djk179.
    1. Leemans C.R., Braakhuis B.J.M., Brakenhoff R.H. The molecular biology of head and neck cancer. Nat. Rev. Cancer. 2010;11:9–22. doi: 10.1038/nrc2982.
    1. Ang K.K., Harris J., Wheeler R., Weber R., Rosenthal D.I., Nguyen-Tân P.F., Westra W.H., Chung C.H., Jordan R.C., Lu C., et al. Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer. N. Engl. J. Med. 2010;363:24–35. doi: 10.1056/NEJMoa0912217.
    1. Leemans C.R., Snijders P.J.F., Brakenhoff R.H. The molecular landscape of head and neck cancer. Nat. Rev. Cancer. 2018;18:269–282. doi: 10.1038/nrc.2018.11.
    1. Machiels J.-P., Leemans C.R., Golusinski W., Grau C., Licitra L., Gregoire V. Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS–ESMO–ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2020;31:1462–1475. doi: 10.1016/j.annonc.2020.07.011.
    1. Pai S.I., Westra W.H. Molecular Pathology of Head and Neck Cancer: Implications for Diagnosis, Prognosis, and Treatment. Annu. Rev. Pathol. Mech. Dis. 2009;4:49–70. doi: 10.1146/annurev.pathol.4.110807.092158.
    1. Fakhry C., Lacchetti C., Rooper L.M., Jordan R.C., Rischin D., Sturgis E.M., Bell D., Lingen M.W., Harichand-Herdt S., Thibo J., et al. Human Papillomavirus Testing in Head and Neck Carcinomas: ASCO Clinical Practice Guideline Endorsement of the College of American Pathologists Guideline. J. Clin. Oncol. 2018;36:3152–3161. doi: 10.1200/JCO.18.00684.
    1. Hashim D., Boffetta P. Head and Neck Cancers. Occup. Cancers. 2020:57–105. doi: 10.1007/978-3-030-30766-0_4.
    1. Le X., Ferrarotto R., Wise-Draper T., Gillison M. Evolving Role of Immunotherapy in Recurrent Metastatic Head and Neck Cancer. J. Natl. Compr. Cancer Netw. 2020;18:899–906. doi: 10.6004/jnccn.2020.7590.
    1. Sacco A.G., Cohen E.E. Current Treatment Options for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. J. Clin. Oncol. 2015;33:3305–3313. doi: 10.1200/JCO.2015.62.0963.
    1. Subbiah V., Solit D., Chan T., Kurzrock R. The FDA approval of pembrolizumab for adult and pediatric patients with tumor mutational burden (TMB) ≥10: A decision centered on empowering patients and their physicians. Ann. Oncol. 2020;31:1115–1118. doi: 10.1016/j.annonc.2020.07.002.
    1. Gavrielatou N., Doumas S., Economopoulou P., Foukas P.G., Psyrri A. Biomarkers for immunotherapy response in head and neck cancer. Cancer Treat. Rev. 2020;84:101977. doi: 10.1016/j.ctrv.2020.101977.
    1. Economopoulou P., De Bree R., Kotsantis I., Psyrri A. Diagnostic Tumor Markers in Head and Neck Squamous Cell Carcinoma (HNSCC) in the Clinical Setting. Front. Oncol. 2019;9:827. doi: 10.3389/fonc.2019.00827.
    1. Mehanna H., Rischin D., Wong S.J., Gregoire V., Ferris R., Waldron J., Le Q.-T., Forster M., Gillison M., Laskar S., et al. De-Escalation After De-Escalate and RTOG 1016: A Head and Neck Cancer InterGroup Framework for Future De-Escalation Studies. J. Clin. Oncol. 2020;38:2552–2557. doi: 10.1200/JCO.20.00056.
    1. Poeta M.L., Manola J., Goldwasser M.A., Forastiere A., Benoit N., Califano J.A., Ridge J.A., Goodwin J., Kenady D., Saunders J., et al. TP53Mutations and Survival in Squamous-Cell Carcinoma of the Head and Neck. N. Engl. J. Med. 2007;357:2552–2561. doi: 10.1056/NEJMoa073770.
    1. Kern S.E. Why Your New Cancer Biomarker May Never Work: Recurrent Patterns and Remarkable Diversity in Biomarker Failures. Cancer Res. 2012;72:6097–6101. doi: 10.1158/0008-5472.CAN-12-3232.
    1. Hunt J.L. Applications of molecular testing in surgical pathology of the head and neck. Mod. Pathol. 2017;30:S104–S111. doi: 10.1038/modpathol.2016.192.
    1. Mandal R., Şenbabaoğlu Y., Desrichard A., Havel J.J., Dalin M.G., Riaz N., Lee K.-W., Ganly I., Hakimi A.A., Chan T.A., et al. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight. 2016;1:e89829. doi: 10.1172/jci.insight.89829.
    1. Ferris R.L. Immunology and Immunotherapy of Head and Neck Cancer. J. Clin. Oncol. 2015;33:3293–3304. doi: 10.1200/JCO.2015.61.1509.
    1. Hanahan D., Weinberg R.A. Hallmarks of Cancer: The Next Generation. Cell. 2011;144:646–674. doi: 10.1016/j.cell.2011.02.013.
    1. Bruni D., Angell H.K., Galon J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat. Rev. Cancer. 2020;20:662–680. doi: 10.1038/s41568-020-0285-7.
    1. Reichert T.E., Rabinowich H., Johnson J.T., Whiteside T.L. Mechanisms Responsible for Signaling and Functional Defects. J. Immunother. 1998;21:295–306. doi: 10.1097/00002371-199807000-00007.
    1. Reichert T.E., Strauss L., Wagner E.M., Gooding W., Whiteside T.L. Signaling abnormalities, apoptosis, and reduced proliferation of circulating and tumor-infiltrating lymphocytes in patients with oral carcinoma. Clin. Cancer Res. 2002;8:3137–3145.
    1. Upreti D., Zhang M.-L., Bykova E., Kung S.K.P., Pathak K.A. Change in CD3ζ-chain expression is an independent predictor of disease status in head and neck cancer patients. Int. J. Cancer. 2016;139:122–129. doi: 10.1002/ijc.30046.
    1. Sakakura K., Chikamatsu K., Takahashi K., Whiteside T.L., Furuya N. Maturation of circulating dendritic cells and imbalance of T-cell subsets in patients with squamous cell carcinoma of the head and neck. Cancer Immunol. Immunother. 2005;55:151–159. doi: 10.1007/s00262-005-0697-y.
    1. Hoffmann T.K., Dworacki G., Tsukihiro T., Meidenbauer N., Gooding W., Johnson J.T., Whiteside T.L. Spontaneous apoptosis of circulating T lymphocytes in patients with head and neck cancer and its clinical importance. Clin. Cancer Res. 2002;8:2553.
    1. De Ruiter E.J., Ooft M.L., Devriese L.A., Willems S.M. The prognostic role of tumor infiltrating T-lymphocytes in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis. OncoImmunology. 2017;6:e1356148. doi: 10.1080/2162402X.2017.1356148.
    1. Strauss L., Bergmann C., Szczepanski M.J., Gooding W.E., Johnson J.T., Whiteside T.L. A Unique Subset of CD4+CD25highFoxp3+ T Cells Secreting Interleukin-10 and Transforming Growth Factor-β1 Mediates Suppression in the Tumor Microenvironment. Clin. Cancer Res. 2007;13:4345–4354. doi: 10.1158/1078-0432.CCR-07-0472.
    1. Bergmann C., Strauss L., Wang Y., Szczepanski M.J., Lang S., Johnson J.T., Whiteside T.L. T Regulatory Type 1 Cells in Squamous Cell Carcinoma of the Head and Neck: Mechanisms of Suppression and Expansion in Advanced Disease. Clin. Cancer Res. 2008;14:3706–3715. doi: 10.1158/1078-0432.CCR-07-5126.
    1. Oweida A., Hararah M.K., Phan A.V., Binder D.C., Bhatia S., Lennon S., Bukkapatnam S., Van Court B., Uyanga N., Darragh L., et al. Resistance to Radiotherapy and PD-L1 Blockade Is Mediated by TIM-3 Upregulation and Regulatory T-Cell Infiltration. Clin. Cancer Res. 2018;24:5368–5380. doi: 10.1158/1078-0432.CCR-18-1038.
    1. Jie H.-B., Gildenerleapman N., Li J., Srivastava R.M., Gibson S.P., Whiteside T.L., Ferris R.L. Intratumoral regulatory T cells upregulate immunosuppressive molecules in head and neck cancer patients. Br. J. Cancer. 2013;109:2629–2635. doi: 10.1038/bjc.2013.645.
    1. Seminerio I., Descamps G., Dupont S., De Marrez L., Laigle J.-A., Lechien J.R., Kindt N., Journe F., Saussez S. Infiltration of FoxP3+ Regulatory T Cells is a Strong and Independent Prognostic Factor in Head and Neck Squamous Cell Carcinoma. Cancers. 2019;11:227. doi: 10.3390/cancers11020227.
    1. Badoual C., Hans S., Rodriguez J., Peyrard S., Klein C., Agueznay N.E.H., Mosseri V., Laccourreye O., Bruneval P., Fridman W.H., et al. Prognostic Value of Tumor-Infiltrating CD4+ T-Cell Subpopulations in Head and Neck Cancers. Clin. Cancer Res. 2006;12:465–472. doi: 10.1158/1078-0432.CCR-05-1886.
    1. Shang B., Liu Y., Jiang S.-J., Liu Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: A systematic review and meta-analysis. Sci. Rep. 2015;5:15179. doi: 10.1038/srep15179.
    1. Lang S., Bruderek K., Kaspar C., Höing B., Kanaan O., Dominas N., Hussain T., Droege F., Eyth C., Hadaschik B., et al. Clinical Relevance and Suppressive Capacity of Human Myeloid-Derived Suppressor Cell Subsets. Clin. Cancer Res. 2018;24:4834–4844. doi: 10.1158/1078-0432.CCR-17-3726.
    1. Greene S., Robbins Y., Mydlarz W.K., Huynh A.P., Schmitt N.C., Friedman J., Horn L.A., Palena C., Schlom J., Maeda D.Y., et al. Inhibition of MDSC Trafficking with SX-682, a CXCR1/2 Inhibitor, Enhances NK-Cell Immunotherapy in Head and Neck Cancer Models. Clin. Cancer Res. 2020;26:1420–1431. doi: 10.1158/1078-0432.CCR-19-2625.
    1. Mantovani A., Sica A., Sozzani S., Allavena P., Vecchi A., Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677–686. doi: 10.1016/j.it.2004.09.015.
    1. She L., Qin Y., Wang J., Liu C., Zhu G., Li G., Wei M., Chen C., Liu G., Zhang D., et al. Tumor-associated macrophages derived CCL18 promotes metastasis in squamous cell carcinoma of the head and neck. Cancer Cell Int. 2018;18:120. doi: 10.1186/s12935-018-0620-1.
    1. Troiano G., Caponio V.C.A., Adipietro I., Tepedino M., Santoro R., Laino L., Russo L.L., Cirillo N., Muzio L.L. Prognostic significance of CD68+ and CD163+ tumor associated macrophages in head and neck squamous cell carcinoma: A systematic review and meta-analysis. Oral Oncol. 2019;93:66–75. doi: 10.1016/j.oraloncology.2019.04.019.
    1. Kumar A.T., Knops A., Swendseid B., Martinez-Outschoom U., Harshyne L., Philp N., Rodeck U., Luginbuhl A., Cognetti D., Johnson J., et al. Prognostic Significance of Tumor-Associated Macrophage Content in Head and Neck Squamous Cell Carcinoma: A Meta-Analysis. Front. Oncol. 2019;9:656. doi: 10.3389/fonc.2019.00656.
    1. Bu L.-L., Yu G.-T., Deng W.-W., Mao L., Liu J.-F., Ma S.-R., Fan T.-F., Hall B., Kulkarni A.B., Zhang W.-F., et al. Targeting STAT3 signaling reduces immunosuppressive myeloid cells in head and neck squamous cell carcinoma. OncoImmunology. 2016;5:e1130206. doi: 10.1080/2162402X.2015.1130206.
    1. Lathers D. Increased aberrance of cytokine expression in plasma of patients with more advanced squamous cell carcinoma of the head and neck. Cytokine. 2004;25:220–228. doi: 10.1016/j.cyto.2003.11.005.
    1. Allen C.T., A Duffy S., Teknos T.N., Islam M., Chen Z., Albert P.S., Wolf G.T., Van Waes C. Nuclear Factor-κB–Related Serum Factors as Longitudinal Biomarkers of Response and Survival in Advanced Oropharyngeal Carcinoma. Clin. Cancer Res. 2007;13:3182–3190. doi: 10.1158/1078-0432.CCR-06-3047.
    1. De Medeiros M.C., Banerjee R., Liu M., Anovazzi G., D’Silva N.J., Junior C.R. HNSCC subverts PBMCs to secrete soluble products that promote tumor cell proliferation. Oncotarget. 2017;8:60860–60874. doi: 10.18632/oncotarget.18486.
    1. White R.A., Malkoski S.P., Wang X.-J. TGFβ signaling in head and neck squamous cell carcinoma. Oncogene. 2010;29:5437–5446. doi: 10.1038/onc.2010.306.
    1. Bornstein S., Schmidt M., Choonoo G., Levin T., Gray J., Thomas C.R., Jr., Wong M., McWeeney S. IL-10 and integrin signaling pathways are associated with head and neck cancer progression. BMC Genom. 2016;17:1–9. doi: 10.1186/s12864-015-2359-6.
    1. Duffy S.A., Taylor J.M.G., Terrell J.E., Islam M., Li Y., Fowler K.E., Wolf G.T., Teknos T.N. Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer. 2008;113:750–757. doi: 10.1002/cncr.23615.
    1. Tsai M.-S., Chen W.-C., Lu C.-H., Chen M.-F. The prognosis of head and neck squamous cell carcinoma related to immunosuppressive tumor microenvironment regulated by IL-6 signaling. Oral Oncol. 2019;91:47–55. doi: 10.1016/j.oraloncology.2019.02.027.
    1. Bergmann C., Strauss L., Zeidler R., Lang S., Whiteside T.L. Expansion of Human T Regulatory Type 1 Cells in the Microenvironment of Cyclooxygenase 2 Overexpressing Head and Neck Squamous Cell Carcinoma. Cancer Res. 2007;67:8865–8873. doi: 10.1158/0008-5472.CAN-07-0767.
    1. Camacho M., León X., Fernández-Figueras M.-T., Quer M., Vila L. Prostaglandin E2pathway in head and neck squamous cell carcinoma. Head Neck. 2008;30:1175–1181. doi: 10.1002/hed.20850.
    1. Lang S., Tiwari S., Andratschke M., Loehr I., Lauffer L., Bergmann C., Mack B., Lebeau A., Moosmann A., Whiteside T.L., et al. Immune restoration in head and neck cancer patients after in vivo COX-2 inhibition. Cancer Immunol. Immunother. 2007;56:1645–1652. doi: 10.1007/s00262-007-0312-5.
    1. Gallo O., Franchi A., Magnelli L., Sardi I., Vannacci A., Boddit V., Chiarugi V., Masini E. Cyclooxygenase-2 Pathway Correlates with VEGF Expression in Head and Neck Cancer. Implications for Tumor Angiogenesis and Metastasis. Neoplasia. 2001;3:53–61. doi: 10.1038/sj.neo.7900127.
    1. Kyzas P.A., Cunha I.W., Ioannidis J.P. Prognostic Significance of Vascular Endothelial Growth Factor Immunohistochemical Expression in Head and Neck Squamous Cell Carcinoma: A Meta-Analysis. Clin. Cancer Res. 2005;11:1434–1440. doi: 10.1158/1078-0432.CCR-04-1870.
    1. Le Q.-T., Shi G., Cao H., Nelson D.W., Wang Y., Chen E.Y., Zhao S., Kong C., Richardson D., O’Byrne K.J., et al. Galectin-1: A Link Between Tumor Hypoxia and Tumor Immune Privilege. J. Clin. Oncol. 2005;23:8932–8941. doi: 10.1200/JCO.2005.02.0206.
    1. Maybruck B.T., Pfannenstiel L.W., Diaz-Montero M., Gastman B.R. Tumor-derived exosomes induce CD8+ T cell suppressors. J. Immunother. Cancer. 2017;5:65. doi: 10.1186/s40425-017-0269-7.
    1. Nambiar D.K., Aguilera T., Cao H., Kwok S., Kong C., Bloomstein J., Wang Z., Rangan V.S., Jiang D., Von Eyben R., et al. Galectin-1–driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance. J. Clin. Investig. 2019;129:5553–5567. doi: 10.1172/JCI129025.
    1. Network T.C.G.A. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nat. Cell Biol. 2015;517:576–582. doi: 10.1038/nature14129.
    1. Ogino T., Shigyo H., Ishii H., Katayama A., Miyokawa N., Harabuchi Y., Ferrone S. HLA Class I Antigen Down-regulation in Primary Laryngeal Squamous Cell Carcinoma Lesions as a Poor Prognostic Marker. Cancer Res. 2006;66:9281–9289. doi: 10.1158/0008-5472.CAN-06-0488.
    1. López-Albaitero A., Nayak J.V., Ogino T., Machandia A., Gooding W., DeLeo A.B., Ferrone S., Ferris R.L. 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. doi: 10.4049/jimmunol.176.6.3402.
    1. Zhou L., Mudianto T., Ma X., Riley R., Uppaluri R. Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti–PD-1 Resistance in Head and Neck Cancer. Clin. Cancer Res. 2019;26:290–300. doi: 10.1158/1078-0432.CCR-19-1351.
    1. Rotte A., Jin J., Lemaire V. Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy. Ann. Oncol. 2018;29:71–83. doi: 10.1093/annonc/mdx686.
    1. Leach D.R., Krummel M.F., Allison J.P. Enhancement of Antitumor Immunity by CTLA-4 Blockade. Science. 1996;271:1734–1736. doi: 10.1126/science.271.5256.1734.
    1. Yu G.-T., Bu L.-L., Zhao Y.-Y., Mao L., Deng W.-W., Wu T.-F., Zhang W.-F., Sun Z.-J. CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma. OncoImmunology. 2016;5:e1151594. doi: 10.1080/2162402X.2016.1151594.
    1. Wang Z., Wu V.H., Allevato M.M., Gilardi M., He Y., Callejas-Valera J.L., Vitale-Cross L., Martin D., Amornphimoltham P., McDermott J., et al. Syngeneic animal models of tobacco-associated oral cancer reveal the activity of in situ anti-CTLA-4. Nat. Commun. 2019;10:1–13. doi: 10.1038/s41467-019-13471-0.
    1. Jie H.-B., Schuler P.J., Lee S.C., Srivastava R.M., Argiris A., Ferrone S., Whiteside T.L., Ferris R.L. 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. doi: 10.1158/0008-5472.CAN-14-2788.
    1. Gao Y., Nihira N.T., Bu X., Chu C., Zhang J., Kolodziejczyk A., Fan Y., Chan N.T., Ma L., Liu J., et al. Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy. Nat. Cell Biol. 2020;22:1–12. doi: 10.1038/s41556-020-0562-4.
    1. Dammeijer F., Van Gulijk M., Mulder E.E., Lukkes M., Klaase L., Bosch T.V.D., Van Nimwegen M., Lau S.P., Latupeirissa K., Schetters S., et al. The PD-1/PD-L1-Checkpoint Restrains T cell Immunity in Tumor-Draining Lymph Nodes. Cancer Cell. 2020;38:685–700.e8. doi: 10.1016/j.ccell.2020.09.001.
    1. Karpathiou G., Casteillo F., Giroult J.-B., Forest F., Fournel P., Monaya A., Froudarakis M., Dumollard J.M., Prades J.M., Peoc’H M. Prognostic impact of immune microenvironment in laryngeal and pharyngeal squamous cell carcinoma: Immune cell subtypes, immuno-suppressive pathways and clinicopathologic characteristics. Oncotarget. 2016;8:19310–19322. doi: 10.18632/oncotarget.14242.
    1. Ock C.-Y., Kim S., Keam B., Kim M., Kim T.M., Kim J.-H., Jeon Y.K., Lee J.-S., Kwon S.K., Hah J.H., et al. PD-L1 expression is associated with epithelial-mesenchymal transition in head and neck squamous cell carcinoma. Oncotarget. 2016;7:15901–15914. doi: 10.18632/oncotarget.7431.
    1. Concha-Benavente F., Srivastava R.M., Trivedi S., Lei Y., Chandran U.R., Seethala R.R., Freeman G.J., Ferris R.L. Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and Neck Cancer. Cancer Res. 2016;76:1031–1043. doi: 10.1158/0008-5472.CAN-15-2001.
    1. Badoual C., Hans S., Merillon N., Van Ryswick C., Ravel P., Benhamouda N., Levionnois E., Nizard M., Si-Mohamed A., Besnier N., et al. PD-1–Expressing Tumor-Infiltrating T Cells Are a Favorable Prognostic Biomarker in HPV-Associated Head and Neck Cancer. Cancer Res. 2012;73:128–138. doi: 10.1158/0008-5472.CAN-12-2606.
    1. Theodoraki M.-N., Yerneni S.S., Hoffmann T.K., Gooding W.E., Whiteside T.L. Clinical Significance of PD-L1+ Exosomes in Plasma of Head and Neck Cancer Patients. Clin. Cancer Res. 2018;24:896–905. doi: 10.1158/1078-0432.CCR-17-2664.
    1. Punt S., Thijssen V.L., Vrolijk J., De Kroon C.D., Gorter A., Jordanova E.S. Galectin-1, -3 and -9 Expression and Clinical Significance in Squamous Cervical Cancer. PLoS ONE. 2015;10:e0129119. doi: 10.1371/journal.pone.0129119.
    1. Workman C.J., Dugger K.J., Vignali D.A.A. Cutting Edge: Molecular Analysis of the Negative Regulatory Function of Lymphocyte Activation Gene-3. J. Immunol. 2002;169:5392–5395. doi: 10.4049/jimmunol.169.10.5392.
    1. Liang B., Workman C., Lee J., Chew C., Dale B.M., Colonna L., Flores M., Li N., Schweighoffer E., Greenberg S., et al. Regulatory T Cells Inhibit Dendritic Cells by Lymphocyte Activation Gene-3 Engagement of MHC Class II. J. Immunol. 2008;180:5916–5926. doi: 10.4049/jimmunol.180.9.5916.
    1. Kouo T.S., Huang L., Pucsek A.B., Cao M., Solt S., Armstrong T.D., Jaffee E.M. Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells. Cancer Immunol. Res. 2015;3:412–423. doi: 10.1158/2326-6066.CIR-14-0150.
    1. Deng W.-W., Mao L., Yu G.-T., Bu L.-L., Ma S.-R., Liu B., Gutkind J.S., Kulkarni A.B., Zhang W.-F., Sun Z.-J. LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma. OncoImmunology. 2016;5:e1239005. doi: 10.1080/2162402X.2016.1239005.
    1. Somasundaram A., Cillo A.R., Lampenfeld C., Oliveri L., Velez M.A., Joyce S., Calderon M.J., Dadey R., Rajasundaram D., Normolle D.P., et al. Systemic Immune Dysfunction in Cancer Patients Driven by IL6 and IL8 Induction of an Inhibitory Receptor Module in Peripheral CD8+ T Cells. bioRxiv. 2020 doi: 10.1101/2020.05.06.081471.
    1. Liu J.-F., Wu L., Yang L.-L., Deng W.-W., Mao L., Wu H., Zhang W.-F., Sun Z.-J. Blockade of TIM3 relieves immunosuppression through reducing regulatory T cells in head and neck cancer. J. Exp. Clin. Cancer Res. 2018;37:1–8. doi: 10.1186/s13046-018-0713-7.
    1. Liu J.-F., Ma S.-R., Mao L., Bu L.-L., Yu G.-T., Li Y.-C., Huang C.-F., Deng W.-W., Kulkarni A.B., Zhang W.-F., et al. T-cell immunoglobulin mucin 3 blockade drives an antitumor immune response in head and neck cancer. Mol. Oncol. 2017;11:235–247. doi: 10.1002/1878-0261.12029.
    1. Wu L., Mao L., Liu J.-F., Chen L., Yu G.-T., Yang L.-L., Wu H., Bu L.-L., Kulkarni A.B., Zhang W.-F., et al. Blockade of TIGIT/CD155 Signaling Reverses T-cell Exhaustion and Enhances Antitumor Capability in Head and Neck Squamous Cell Carcinoma. Cancer Immunol. Res. 2019;7:1700–1713. doi: 10.1158/2326-6066.CIR-18-0725.
    1. Gameiro S.F., Ghasemi F., Barrett J.W., Koropatnick J., Nichols A.C., Mymryk J.S., Vareki S.M. Treatment-naïve HPV+ head and neck cancers display a T-cell-inflamed phenotype distinct from their HPV- counterparts that has implications for immunotherapy. OncoImmunology. 2018;7:e1498439. doi: 10.1080/2162402X.2018.1498439.
    1. Seiwert T.Y., Burtness B., Mehra R., Weiss J., Berger R., Eder J.P., Heath K., McClanahan T., Lunceford J., Gause C., 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;17:956–965. doi: 10.1016/S1470-2045(16)30066-3.
    1. Chow L.Q., Haddad R., Gupta S., Mahipal A., Mehra R., Tahara M., Berger R., Eder J.P., Burtness B., Lee S.-H., 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;34:3838–3845. doi: 10.1200/JCO.2016.68.1478.
    1. Bauml J., Seiwert T.Y., Pfister D.G., Worden F., Liu S.V., Gilbert J., Saba N.F., Weiss J., Wirth L., Sukari A., et al. Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study. J. Clin. Oncol. 2017;35:1542–1549. doi: 10.1200/JCO.2016.70.1524.
    1. Ferris R.L., Blumenschein G., Jr., Fayette J., Guigay J., Colevas A.D., Licitra L., Harrington K., Kasper S., Vokes E.E., Even C., et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N. Engl. J. Med. 2016;375:1856–1867. doi: 10.1056/NEJMoa1602252.
    1. Cohen E.E.W., Soulières D., Le Tourneau C., Dinis J., Licitra L., Ahn M.-J., Soria A., Machiels J.-P., Mach N., Mehra R., et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): A randomised, open-label, phase 3 study. Lancet. 2019;393:156–167. doi: 10.1016/S0140-6736(18)31999-8.
    1. Burtness B., Harrington K.J., Greil R., Soulières D., Tahara M., de Castro G., Psyrri A., Basté N., Neupane P., Bratland Å., et al. 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. doi: 10.1016/S0140-6736(19)32591-7.
    1. Yu Y., Lee N.Y. JAVELIN Head and Neck 100: A Phase III trial of avelumab and chemoradiation for locally advanced head and neck cancer. Futur. Oncol. 2019;15:687–694. doi: 10.2217/fon-2018-0405.
    1. Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer. 2012;12:252–264. doi: 10.1038/nrc3239.
    1. Callahan M.K., Wolchok J.D., Allison J.P. Anti–CTLA-4 Antibody Therapy: Immune Monitoring During Clinical Development of a Novel Immunotherapy. Semin. Oncol. 2010;37:473–484. doi: 10.1053/j.seminoncol.2010.09.001.
    1. Ferris R., Haddad R., Even C., Tahara M., Dvorkin M., Ciuleanu T., Clement P., Mesia R., Kutukova S., Zholudeva L., et al. Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study. Ann. Oncol. 2020;31:942–950. doi: 10.1016/j.annonc.2020.04.001.
    1. Klinghammer K.F., Gauler T.C., Stromberger C., Kofla G., De Wit M., Gollrad J., Rauer I., Martus P., Tinhofer I., Budach V., et al. DURTRERAD: A phase II open-label study evaluating feasibility and efficacy of durvalumab (D) and durvalumab and tremelimumab (DT) in combination with radiotherapy (RT) in non-resectable locally advanced HPV-negative HNSCC—Results of the preplanned feasibility interim analysis. J. Clin. Oncol. 2020;38:6574. doi: 10.1200/jco.2020.38.15_suppl.6574.
    1. Machiels J.-P., Tao Y., Burtness B., Tahara M., Licitra L., Rischin D., Waldron J., Simon C., Gregoire V., Harrington K., et al. Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412. Futur. Oncol. 2020;16:1235–1243. doi: 10.2217/fon-2020-0184.
    1. Massarelli E., William W., Johnson F., Kies M., Ferrarotto R., Guo M., Feng L., Lee J.J., Tran H., Kim Y.U., et al. Combining Immune Checkpoint Blockade and Tumor-Specific Vaccine for Patients With Incurable Human Papillomavirus 16–Related Cancer. JAMA Oncol. 2019;5:67–73. doi: 10.1001/jamaoncol.2018.4051.
    1. Le Tourneau C., Delord J.-P., Cassier P., Loirat D., Tavernaro A., Bastien B., Bendjama K. Phase Ib/II trial of TG4001 (Tipapkinogene sovacivec), a therapeutic HPV-vaccine, and Avelumab in patients with recurrent/metastatic (R/M) HPV-16+ cancers. Ann. Oncol. 2019;30:v494–v495. doi: 10.1093/annonc/mdz253.036.
    1. Stafford M., Kaczmar J. The neoadjuvant paradigm reinvigorated: A review of pre-surgical immunotherapy in HNSCC. Cancers Head Neck. 2020;5:4–9. doi: 10.1186/s41199-020-00052-8.
    1. Uppaluri R., Campbell K.M., Egloff A.M., Zolkind P., Skidmore Z.L., Nussenbaum B., Paniello R.C., Rich J.T., Jackson R., Pipkorn P., et al. Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase 2 Trial. Clin. Cancer Res. 2020;26:5140–5152. doi: 10.1158/1078-0432.CCR-20-1695.
    1. Ferris R., Gonçalves A., Baxi S., Martens U., Gauthier H., Langenberg M., Spanos W., Leidner R., Kang H., Russell J., et al. An open-label, multicohort, phase 1/2 study in patients with virus-associated cancers (CheckMate 358): Safety and efficacy of neoadjuvant nivolumab in squamous cell carcinoma of the head and neck (SCCHN) Ann. Oncol. 2017;28:v628–v629. doi: 10.1093/annonc/mdx440.041.
    1. Wise-Draper T.M., Old M.O., Worden F.P., O’Brien P.E., Cohen E.E., Dunlap N., Mierzwa M.L., Casper K., Palackdharry S., Hinrichs B., et al. Phase II multi-site investigation of neoadjuvant pembrolizumab and adjuvant concurrent radiation and pembrolizumab with or without cisplatin in resected head and neck squamous cell carcinoma. J. Clin. Oncol. 2018;36:6017. doi: 10.1200/JCO.2018.36.15_suppl.6017.
    1. Wong D.J., Fayette J., Guo Y., Kowgier M., Cohen E., Nin R.M., Dechaphunkul A., Prabhash K., Geiger J., Bishnoi S., et al. Clinical Trials. American Association for Cancer Research (AACR); Philadelphia, PA, USA: 2019. Abstract CT123: IMvoke010: Randomized Phase III study of atezolizumab as adjuvant monotherapy after definitive therapy of squamous cell carcinoma of the head and neck (SCCHN)
    1. Busch C.-J., Muenscher A., Betz C.S., Dogan V., Schafhausen P., Bokemeyer C., Binder M. Multicenter randomized controlled phase III study of nivolumab alone or in combination with ipilimumab as immunotherapy vs standard follow-up in surgical resectable HNSCC after adjuvant therapy. J. Clin. Oncol. 2019;37:TPS6095. doi: 10.1200/JCO.2019.37.15_suppl.TPS6095.
    1. Cohen E.E.W., Bell R.B., Bifulco C.B., Burtness B., Gillison M.L., Harrington K.J., Le Q.-T., Lee N.Y., Leidner R., Lewis R.L., et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC) J. Immunother. Cancer. 2019;7:184. doi: 10.1186/s40425-019-0662-5.
    1. Hegde P.S., Chen D.S. Top 10 Challenges in Cancer Immunotherapy. Immunity. 2020;52:17–35. doi: 10.1016/j.immuni.2019.12.011.
    1. Mckean W.B., Moser J.C., Rimm D., Hu-Lieskovan S. Biomarkers in Precision Cancer Immunotherapy: Promise and Challenges. Am. Soc. Clin. Oncol. Educ. Book. 2020;40:e275–e291. doi: 10.1200/EDBK_280571.
    1. Le D.T., Durham J.N., Smith K.N., Wang H., Bartlett B.R., Aulakh L.K., Lu S., Kemberling H., Wilt C., Luber B.S., et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–413. doi: 10.1126/science.aan6733.
    1. Havel J.J., Chowell D., Chan T.A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer. 2019;19:133–150. doi: 10.1038/s41568-019-0116-x.
    1. Samstein R.M., Lee C.-H., Shoushtari A.N., Hellmann M.D., Shen R., Janjigian Y.Y., Barron D.A., Zehir A., Jordan E.J., Omuro A., et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 2019;51:202–206. doi: 10.1038/s41588-018-0312-8.
    1. Cristescu R., Mogg R., Ayers M., Albright A., Murphy E., Yearley J., Sher X., Liu X.Q., Lu H., Nebozhyn M., et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy. Science. 2018;362:eaar3593. doi: 10.1126/science.aar3593.
    1. De La Iglesia J.V., Slebos R.J., Martin-Gomez L., Wang X., Teer J.K., Tan A.C., Gerke T.A., Aden-Buie G., Van Veen T., Masannat J., et al. Effects of Tobacco Smoking on the Tumor Immune Microenvironment in Head and Neck Squamous Cell Carcinoma. Clin. Cancer Res. 2020;26:1474–1485. doi: 10.1158/1078-0432.CCR-19-1769.
    1. Desrichard A., Kuo F., Chowell D., Lee K.-W., Riaz N., Wong R.J., A Chan T., Morris L.G.T. Tobacco Smoking-Associated Alterations in the Immune Microenvironment of Squamous Cell Carcinomas. J. Natl. Cancer Inst. 2018;110:1386–1392. doi: 10.1093/jnci/djy060.
    1. Rizvi N.A., Hellmann M.D., Snyder A., Kvistborg P., Makarov V., Havel J.J., Lee W., Yuan J., Wong P., Ho T.S., et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science. 2015;348:124–128. doi: 10.1126/science.aaa1348.
    1. Kreimer A.R., Clifford G.M., Boyle P., Franceschi S. Human Papillomavirus Types in Head and Neck Squamous Cell Carcinomas Worldwide: A Systematic Review. Cancer Epidemiol. Biomark. Prev. 2005;14:467–475. doi: 10.1158/1055-9965.EPI-04-0551.
    1. Davis A.A., Patel V.G. The role of PD-L1 expression as a predictive biomarker: An analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J. Immunother. Cancer. 2019;7:1–8. doi: 10.1186/s40425-019-0768-9.
    1. Rasmussen J.H., Lelkaitis G., Håkansson K., Vogelius I.R., Johannesen H.H., Fischer B.M., Bentzen S.M., Specht L., Kristensen C.A., Von Buchwald C., et al. Intratumor heterogeneity of PD-L1 expression in head and neck squamous cell carcinoma. Br. J. Cancer. 2019;120:1003–1006. doi: 10.1038/s41416-019-0449-y.
    1. Hong L., Negrao M.V., Dibaj S.S., Chen R., Reuben A., Bohac J.M., Liu X., Skoulidis F., Gay C.M., Cascone T., et al. Programmed Death-Ligand 1 Heterogeneity and Its Impact on Benefit From Immune Checkpoint Inhibitors in NSCLC. J. Thorac. Oncol. 2020;15:1449–1459. doi: 10.1016/j.jtho.2020.04.026.
    1. De Ruiter E.J., Mulder F.J., Koomen B.M., Speel E.-J., Hout M.F.C.M.V.D., De Roest R.H., Bloemena E., Devriese L.A., Willems S.M. Comparison of three PD-L1 immunohistochemical assays in head and neck squamous cell carcinoma (HNSCC) Mod. Pathol. 2020:1–8. doi: 10.1038/s41379-020-0644-7.
    1. Daassi D., Mahoney K.M., Freeman G.J. The importance of exosomal PDL1 in tumour immune evasion. Nat. Rev. Immunol. 2020;20:209–215. doi: 10.1038/s41577-019-0264-y.
    1. Theodoraki M.-N., Yerneni S., Gooding W.E., Ohr J., Clump D.A., Bauman J.E., Ferris R.L., Whiteside T.L. Circulating exosomes measure responses to therapy in head and neck cancer patients treated with cetuximab, ipilimumab, and IMRT. OncoImmunology. 2019;8:e1593805. doi: 10.1080/2162402X.2019.1593805.
    1. Ayers M., Lunceford J., Nebozhyn M., Murphy E., Loboda A., Kaufman D.R., Albright A., Cheng J.D., Kang S.P., Shankaran V., et al. IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Investig. 2017;127:2930–2940. doi: 10.1172/JCI91190.
    1. Chen Y.-P., Wang Y.-Q., Lv J.-W., Li Y.-Q., Chua M., Le Q.-T., Lee N., Colevas A.D., Seiwert T., Hayes D., et al. Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: Implications for immunotherapy. Ann. Oncol. 2019;30:68–75. doi: 10.1093/annonc/mdy470.
    1. Ren X., Kang B., Zhang Z. Understanding tumor ecosystems by single-cell sequencing: Promises and limitations. Genome Biol. 2018;19:211. doi: 10.1186/s13059-018-1593-z.
    1. Puram S.V., Tirosh I., Parikh A.S., Patel A.P., Yizhak K., Gillespie S., Rodman C., Luo C.L., Mroz E.A., Emerick K.S., et al. Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer. Cell. 2017;171:1611–1624.e24. doi: 10.1016/j.cell.2017.10.044.
    1. Börnigen D., Ren B., Pickard R., Li J., Ozer E., Hartmann E.M., Xiao W., Tickle T., Rider J., Gevers D., et al. Alterations in oral bacterial communities are associated with risk factors for oral and oropharyngeal cancer. Sci. Rep. 2017;7:1–13. doi: 10.1038/s41598-017-17795-z.
    1. Hayes R.B., Ahn J., Fan X., Peters B.A., Ma Y., Yang L., Agalliu I., Burk R.D., Ganly I., Purdue M.P., et al. Association of Oral Microbiome With Risk for Incident Head and Neck Squamous Cell Cancer. JAMA Oncol. 2018;4:358–365. doi: 10.1001/jamaoncol.2017.4777.
    1. Garrett W.S. Cancer and the microbiota. Science. 2015;348:80–86. doi: 10.1126/science.aaa4972.
    1. Routy B., Gopalakrishnan V., Daillère R., Zitvogel L., Wargo J.A., Kroemer G. The gut microbiota influences anticancer immunosurveillance and general health. Nat. Rev. Clin. Oncol. 2018;15:382–396. doi: 10.1038/s41571-018-0006-2.
    1. Gopalakrishnan V., Spencer C.N., Nezi L., Reuben A., Andrews M.C., Karpinets T.V., Prieto P.A., Vicente D., Hoffman K., Wei S.C., et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018;359:97–103. doi: 10.1126/science.aan4236.
    1. Zheng Y., Wang T., Tu X., Huang Y., Zhang H., Tan D., Jiang W., Cai S., Zhao P., Song R., et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J. Immunother. Cancer. 2019;7:193. doi: 10.1186/s40425-019-0650-9.
    1. Wang S., He Z., Wang X., Li H., Liu X.-S. Antigen presentation and tumor immunogenicity in cancer immunotherapy response prediction. eLife. 2019;8:8. doi: 10.7554/eLife.49020.
    1. Charoentong P., Finotello F., Angelova M., Mayer C., Efremova M., Rieder D., Hackl H., Trajanoski Z. Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade. Cell Rep. 2017;18:248–262. doi: 10.1016/j.celrep.2016.12.019.
    1. Lu S., Stein J.E., Rimm D.L., Wang D.W., Bell J.M., Johnson D.B., Sosman J.A., Schalper K.A., Anders R.A., Wang H., et al. Comparison of Biomarker Modalities for Predicting Response to PD-1/PD-L1 Checkpoint Blockade. JAMA Oncol. 2019;5:1195–1204. doi: 10.1001/jamaoncol.2019.1549.
    1. Van Schalkwyk M.C.I., Papa S.E., Jeannon J.-P., Urbano T.G., Spicer J.F., Maher J. Design of a Phase I Clinical Trial to Evaluate Intratumoral Delivery of ErbB-Targeted Chimeric Antigen Receptor T-Cells in Locally Advanced or Recurrent Head and Neck Cancer. Hum. Gene Ther. Clin. Dev. 2013;24:134–142. doi: 10.1089/humc.2013.144.
    1. June C.H., O’Connor R.S., Kawalekar O.U., Ghassemi S., Milone M.C. CAR T cell immunotherapy for human cancer. Science. 2018;359:1361–1365. doi: 10.1126/science.aar6711.
    1. Mei Z., Zhang K., Lam A.K., Huang J., Qiu F., Qiao B., Zhang Y. MUC1 as a target for CAR-T therapy in head and neck squamous cell carinoma. Cancer Med. 2019;9:640–652. doi: 10.1002/cam4.2733.

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