Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous disease that affects more than 800,000 patients worldwide each year. The variability of HNSCC is associated with differences in the carcinogenesis processes that are caused by two major etiological agents, namely, alcohol/tobacco, and human papillomavirus (HPV). Compared to non-virally induced carcinomas, the oropharyngeal tumors associated with HPV infection show markedly better clinical outcomes and are characterized by an immunologically "hot" landscape with high levels of tumor-infiltrating lymphocytes. However, the standard of care remains the same for both HPV-positive and HPV-negative HNSCC. Surprisingly, treatment de-escalation trials have not shown any clinical benefit in patients with HPV-positive tumors to date, most likely due to insufficient patient stratification. The in-depth analysis of the immune response, which places an emphasis on tumor-infiltrating immune cells, is a widely accepted prognostic tool that might significantly improve both the stratification of HNSCC patients in de-escalation trials and the development of novel immunotherapeutic approaches.

BioGraphix Hluboká nad Vltavou Czechia

Department of Otorhinolaryngology and Head and Neck Surgery 1st Faculty of Medicine Charles University and University Hospital Motol Prague Czechia

Sotio Prague Czechia

Zobrazit více v PubMed

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, 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. 10.3322/caac.21492 PubMed DOI

Lajer CB, von Buchwald C. The role of human papillomavirus in head and neck cancer. APMIS. (2010) 118:510–9. 10.1111/j.1600-0463.2010.02624.x PubMed DOI

D'Souza G, Dempsey A. The role of HPV in head and neck cancer and review of the HPV vaccine. Prev Med. (2011) 53 (Suppl. 1):S5–S11. 10.1016/j.ypmed.2011.08.001 PubMed DOI PMC

Rautava J, Syrjanen S. Biology of human papillomavirus infections in head and neck carcinogenesis. Head Neck Pathol. (2012) 6 (Suppl. 1):S3–15. 10.1007/s12105-012-0367-2 PubMed DOI PMC

zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. (2002) 2:342–50. 10.1038/nrc798 PubMed DOI

Taberna M, Mena M, Pavon MA, Alemany L, Gillison ML, Mesia R. Human papillomavirus-related oropharyngeal cancer. Ann Oncol. (2017) 28:2386–98. 10.1093/annonc/mdx304 PubMed DOI

Faraji F, Zaidi M, Fakhry C, Gaykalova DA. Molecular mechanisms of human papillomavirus-related carcinogenesis in head and neck cancer. Microbes Infect. (2017) 19:464–75. 10.1016/j.micinf.2017.06.001 PubMed DOI PMC

Canning M, Guo G, Yu M, Myint C, Groves MW, Byrd JK, et al. . Heterogeneity of the head and neck squamous cell carcinoma immune landscape and its impact on immunotherapy. Front Cell Dev Biol. (2019) 7:52. 10.3389/fcell.2019.00052 PubMed DOI PMC

Munger K, Phelps WC, Bubb V, Howley PM, Schlegel R. The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol. (1989) 63:4417–21. 10.1128/JVI.63.10.4417-4421.1989 PubMed DOI PMC

Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. (1990) 63:1129–36. 10.1016/0092-8674(90)90409-8 PubMed DOI

Kim SH, Koo BS, Kang S, Park K, Kim H, Lee KR, et al. . HPV integration begins in the tonsillar crypt and leads to the alteration of p16, EGFR and c-myc during tumor formation. Int J Cancer. (2007) 120:1418–25. 10.1002/ijc.22464 PubMed DOI

Maleki Vareki S. High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J Immunother Cancer. (2018) 6:157. 10.1186/s40425-018-0479-7 PubMed DOI PMC

Eder T, Hess AK, Konschak R, Stromberger C, Jöhrens K, Fleischer V, et al. . Interference of tumour mutational burden with outcome of patients with head and neck cancer treated with definitive chemoradiation: a multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group. Eur J Cancer. (2019) 116:67–76. 10.1016/j.ejca.2019.04.015 PubMed DOI

Henderson S, Fenton T. APOBEC3 genes: retroviral restriction factors to cancer drivers. Trends Mol Med. (2015) 21:274–84. 10.1016/j.molmed.2015.02.007 PubMed DOI

Faden DL, Ding F, Lin Y, Zhai S, Kuo F, Chan TA, et al. . APOBEC mutagenesis is tightly linked to the immune landscape and immunotherapy biomarkers in head and neck squamous cell carcinoma. Oral Oncol. (2019) 96:140–7. 10.1016/j.oraloncology.2019.07.020 PubMed DOI PMC

Vogelmann R, Amieva MR. The role of bacterial pathogens in cancer. Curr Opin Microbiol. (2007) 10:76–81. 10.1016/j.mib.2006.12.004 PubMed DOI

Whitmore SE, Lamont RJ. Oral bacteria and cancer. PLoS Pathog. (2014) 10:e1003933. 10.1371/journal.ppat.1003933 PubMed DOI PMC

Wolf A, Moissl-Eichinger C, Perras A, Koskinen K, Tomazic PV, Thurnher D. The salivary microbiome as an indicator of carcinogenesis in patients with oropharyngeal squamous cell carcinoma: a pilot study. Sci Rep. (2017) 7:5867. 10.1038/s41598-017-06361-2 PubMed DOI PMC

Licitra L, Perrone F, Bossi P, Suardi S, Mariani L, Artusi R, et al. . High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol. (2006) 24:5630–6. 10.1200/JCO.2005.04.6136 PubMed DOI

Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, et al. . Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. (2008) 100:261–9. 10.1093/jnci/djn011 PubMed DOI

Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol. (2009) 27:1992–8. 10.1200/JCO.2008.20.2853 PubMed DOI

Lydiatt WM, Patel SG, O'Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, et al. . Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. (2017) 67:122–37. 10.3322/caac.21389 PubMed DOI

Fouret P, Martin F, Flahault A, Saint-Guily JL. Human papillomavirus infection in the malignant and premalignant head and neck epithelium. Diagn Mol Pathol. (1995) 4:122–7. 10.1097/00019606-199506000-00008 PubMed DOI

Benson E, Li R, Eisele D, Fakhry C. The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas. Oral Oncol. (2014) 50:565–74. 10.1016/j.oraloncology.2013.09.008 PubMed DOI PMC

Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, et al. . Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. (2010) 363:24–35. 10.1056/NEJMoa0912217 PubMed DOI PMC

Ward MJ, Thirdborough SM, Mellows T, Riley C, Harris S, Suchak K, et al. . Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer. Br J Cancer. (2014) 110:489–500. 10.1038/bjc.2013.639 PubMed DOI PMC

Holmes BJ, Wenig BM. Virus-associated carcinomas of the head & neck: Update from the 2017 WHO classification. Ann Diagn Pathol. (2019) 38:29–42. 10.1016/j.anndiagpath.2018.10.008 PubMed DOI

Seiwert TY, Zuo Z, Keck MK, Khattri A, Pedamallu CS, Stricker T, et al. . Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin Cancer Res. (2015) 21:632–41. 10.1158/1078-0432.CCR-13-3310 PubMed DOI PMC

Partlová S, Bouček J, Kloudová K, Lukešová E, Zábrodský M, Grega M, et al. . Distinct patterns of intratumoral immune cell infiltrates in patients with HPV-associated compared to non-virally induced head and neck squamous cell carcinoma. Oncoimmunology. (2015) 4:e965570. 10.4161/21624011.2014.965570 PubMed DOI PMC

Chakravarthy A, Henderson S, Thirdborough SM, Ottensmeier CH, Su X, Lechner M, et al. . Human papillomavirus drives tumor development throughout the head and neck: improved prognosis is associated with an immune response largely restricted to the oropharynx. J Clin Oncol. (2016) 34:4132–41. 10.1200/JCO.2016.68.2955 PubMed DOI PMC

Adelstein DJ, Ridge JA, Gillison ML, Chaturvedi AK, D'Souza G, Gravitt PE, et al. . Head and neck squamous cell cancer and the human papillomavirus: summary of a National Cancer Institute State of the Science Meeting, November 9-10, 2008 Washington, D.C. Head Neck. (2009) 31:1393–422. 10.1002/hed.21269 PubMed DOI

Kelly JR, Husain ZA, Burtness B. Treatment de-intensification strategies for head and neck cancer. Eur J Cancer. (2016) 68:125–33. 10.1016/j.ejca.2016.09.006 PubMed DOI PMC

Gillison ML, Zhang Q, Jordan R, Xiao W, Westra WH, Trotti A, et al. . Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer. J Clin Oncol. (2012) 30:2102–11. 10.1200/JCO.2011.38.4099 PubMed DOI PMC

Granata R, Miceli R, Orlandi E, Perrone F, Cortelazzi B, Franceschini M, et al. . Tumor stage, human papillomavirus and smoking status affect the survival of patients with oropharyngeal cancer: an Italian validation study. Ann Oncol. (2012) 23:1832–7. 10.1093/annonc/mdr544 PubMed DOI

Mandal R, Senbabaoglu Y, Desrichard A, Havel JJ, Dalin MG, Riaz N, Lee KW, et al. . The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight. (2016) 1:e89829. 10.1172/jci.insight.89829 PubMed DOI PMC

Näsman A, Romanitan M, Nordfors C, Grün N, Johansson H, Hammarstedt L, et al. . Tumor infiltrating CD8+ and Foxp3+ lymphocytes correlate to clinical outcome and human papillomavirus (HPV) status in tonsillar cancer. PLoS ONE. (2012) 7:e38711. 10.1371/journal.pone.0038711 PubMed DOI PMC

Gameiro SF, Ghasemi F, Barrett JW, Koropatnick J, Nichols AC, Mymryk JS, et al. . Treatment-naive 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. 10.1080/2162402X.2018.1498439 PubMed DOI PMC

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. . Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. (2006) 313:1960–4. 10.1126/science.1129139 PubMed DOI

Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, et al. . Towards the introduction of the 'Immunoscore' in the classification of malignant tumours. J Pathol. (2014) 232:199–209. 10.1002/path.4287 PubMed DOI PMC

Kawai O, Ishii G, Kubota K, Murata Y, Naito Y, Mizuno T, et al. . Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer. (2008) 113:1387–95. 10.1002/cncr.23712 PubMed DOI

Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. . Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. (2005) 102:18538–43. 10.1073/pnas.0509182102 PubMed DOI PMC

Solomon B, Young RJ, Bressel M, Urban D, Hendry S, Thai A, et al. . Prognostic Significance of PD-L1(+) and CD8(+) Immune Cells in HPV(+) oropharyngeal squamous cell carcinoma. Cancer Immunol Res. (2018) 6:295–304. 10.1158/2326-6066.CIR-17-0299 PubMed DOI

Hladíková K, Koucký V, Bouček J, Laco J, Grega M, Hodek M, et al. . Tumor-infiltrating B cells affect the progression of oropharyngeal squamous cell carcinoma via cell-to-cell interactions with CD8(+) T cells. J Immunother Cancer. (2019) 7:261. 10.1186/s40425-019-0726-6 PubMed DOI PMC

Burnet FM. Cancer a biological approach. Br Med J. (1957) 1:841–7. 10.1136/bmj.1.5023.841 PubMed DOI PMC

Boshoff C, Weiss R. AIDS-related malignancies. Nat Rev Cancer. (2002) 2:373–82. 10.1038/nrc797 PubMed DOI

Engels EA, Pfeiffer RM, Fraumeni JF, Jr, Kasiske BL, Israni AK, Snyder JJ, et al. . Spectrum of cancer risk among US solid organ transplant recipients. JAMA. (2011) 306:1891–901. 10.1001/jama.2011.1592 PubMed DOI PMC

Duray A, Demoulin S, Hubert P, Delvenne P, Saussez S. Immune suppression in head and neck cancers: a review. Clin Dev Immunol. (2010) 2010:701657. 10.1155/2010/701657 PubMed DOI PMC

Costello RT, Gastaut JA, Olive D. Tumor escape from immune surveillance. Arch Immunol Ther Exp (Warsz). (1999) 47:83–88. PubMed

Chen X, Yan B, Lou H, Shen Z, Tong F, Zhai A, et al. . Immunological network analysis in HPV associated head and neck squamous cancer and implications for disease prognosis. Mol Immunol. (2018) 96:28–36. 10.1016/j.molimm.2018.02.005 PubMed DOI

Wagner S, Wittekindt C, Reuschenbach M, Hennig B, Thevarajah M, Würdemann N, et al. . CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma. Int J Cancer. (2016) 138:2263–73. 10.1002/ijc.29962 PubMed DOI

Gallo O, Libonati GA, Gallina E, Fini-Storchi O, Giannini A, Urso C, et al. . Langerhans cells related to prognosis in patients with laryngeal carcinoma. Arch Otolaryngol Head Neck Surg. (1991) 117:1007–10. 10.1001/archotol.1991.01870210079015 PubMed DOI

Goldman SA, Baker E, Weyant RJ, Clarke MR, Myers JN, Lotze MT. Peritumoral CD1a-positive dendritic cells are associated with improved survival in patients with tongue carcinoma. Arch Otolaryngol Head Neck Surg. (1998) 124:641–6. 10.1001/archotol.124.6.641 PubMed DOI

Reichert TE, Scheuer C, Day R, Wagner W, Whiteside TL. The number of intratumoral dendritic cells and zeta-chain expression in T cells as prognostic and survival biomarkers in patients with oral carcinoma. Cancer. (2001) 91:2136–47. 10.1002/1097-0142(20010601)91:11<2136::AID-CNCR1242>3.0.CO;2-Q PubMed DOI

Kindt N, Descamps G, Seminerio I, Bellier J, Lechien JR, Pottier C, et al. . Langerhans cell number is a strong and independent prognostic factor for head and neck squamous cell carcinomas. Oral Oncol. (2016) 62:1–10. 10.1016/j.oraloncology.2016.08.016 PubMed DOI

O'Donnell RK, Mick R, Feldman M, Hino S, Wang Y, Brose MS, et al. . Distribution of dendritic cell subtypes in primary oral squamous cell carcinoma is inconsistent with a functional response. Cancer Lett. (2007) 255:145–52. 10.1016/j.canlet.2007.04.003 PubMed DOI PMC

Han N, Zhang Z, Liu S, Ow A, Ruan M, Yang W, et al. . Increased tumor-infiltrating plasmacytoid dendritic cells predicts poor prognosis in oral squamous cell carcinoma. Arch Oral Biol. (2017) 78:129–34. 10.1016/j.archoralbio.2017.02.012 PubMed DOI

Nordfors C, Grün N, Tertipis N, Ährlund-Richter A, Haeggblom L, Sivars L, Du J, et al. . 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) 49:2522–30. 10.1016/j.ejca.2013.03.019 PubMed DOI

Badoual C, Hans S, Merillon N, Van Ryswick C, Ravel P, Benhamouda N, et al. . PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. (2013) 73:128–38. 10.1158/0008-5472.CAN-12-2606 PubMed DOI

Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay Nel H, et al. . Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res. (2006) 12:465–72. 10.1158/1078-0432.CCR-05-1886 PubMed DOI

Sun J, Tang DN, Fu T, Sharma P. Identification of human regulatory T cells in the setting of T-cell activation and anti-CTLA-4 immunotherapy on the basis of expression of latency-associated peptide. Cancer Discov. (2012) 2:122–30. 10.1158/2159-8290.CD-11-0236 PubMed DOI

Bron L, Jandus C, Andrejevic-Blant S, Speiser DE, Monnier P, Romero P, et al. . Prognostic value of arginase-II expression and regulatory T-cell infiltration in head and neck squamous cell carcinoma. Int J Cancer. (2013) 132:E85–93. 10.1002/ijc.27728 PubMed DOI

Hanakawa H, Orita Y, Sato Y, Takeuchi M, Ohno K, Gion Y, et al. . Regulatory T-cell infiltration in tongue squamous cell carcinoma. Acta Otolaryngol. (2014) 134:859–64. 10.3109/00016489.2014.918279 PubMed DOI

Santegoets SJ, Duurland CL, Jordanova ES, van Ham JJ, Ehsan I, van Egmond SL, et al. . Tbet-positive regulatory T cells accumulate in oropharyngeal cancers with ongoing tumor-specific type 1 T cell responses. J Immunother Cancer. (2019) 7:14. 10.1186/s40425-019-0497-0 PubMed DOI PMC

Zhou X, Su YX, Lao XM, Liang YJ, Liao GQ. CD19(+)IL-10(+) regulatory B cells affect survival of tongue squamous cell carcinoma patients and induce resting CD4(+) T cells to CD4(+)Foxp3(+) regulatory T cells. Oral Oncol. (2016) 53:27–35. 10.1016/j.oraloncology.2015.11.003 PubMed DOI

Italiani P, Boraschi D. From Monocytes to M1/M2 Macrophages: phenotypical vs. functional differentiation. Front Immunol. (2014) 5:514. 10.3389/fimmu.2014.00514 PubMed DOI PMC

Corraliza IM, Soler G, Eichmann K, Modolell M. Arginase induction by suppressors of nitric oxide synthesis (IL-4, IL-10 and PGE2) in murine bone-marrow-derived macrophages. Biochem Biophys Res Commun. (1995) 206:667–73. 10.1006/bbrc.1995.1094 PubMed DOI

Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. (2010) 141:39–51. 10.1016/j.cell.2010.03.014 PubMed DOI PMC

Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. (2014) 6:13. 10.12703/P6-13 PubMed DOI PMC

Rath M, Muller I, Kropf P, Closs EI, Munder M. Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Front Immunol. (2014) 5:532 10.3389/fimmu.2014.00532 PubMed DOI PMC

Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel). (2014) 6:1670–90. 10.3390/cancers6031670 PubMed DOI PMC

Davis RJ, Van Waes C, Allen CT. Overcoming barriers to effective immunotherapy: MDSCs, TAMs, and Tregs as mediators of the immunosuppressive microenvironment in head and neck cancer. Oral Oncol. (2016) 58:59–70. 10.1016/j.oraloncology.2016.05.002 PubMed DOI PMC

Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. . Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. (2004) 10:942–9. 10.1038/nm1093 PubMed DOI

Fialova A, Partlová S, Sojka L, Hromádková H, Brtnický T, Fučíková J, et al. . Dynamics of T-cell infiltration during the course of ovarian cancer: the gradual shift from a Th17 effector cell response to a predominant infiltration by regulatory T-cells. Int J Cancer. (2013) 132:1070–9. 10.1002/ijc.27759 PubMed DOI

Costa NL, Valadares MC, Souza PP, Mendonça EF, Oliveira JC, Silva TA, et al. . Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma. Oral Oncol. (2013) 49:216–23. 10.1016/j.oraloncology.2012.09.012 PubMed DOI

Petruzzi MN, Cherubini K, Salum FG, de Figueiredo MA. Role of tumour-associated macrophages in oral squamous cells carcinoma progression: an update on current knowledge. Diagn Pathol. (2017) 12:32. 10.1186/s13000-017-0623-6 PubMed DOI PMC

He KF, Zhang L, Huang CF, Ma SR, Wang YF, Wang WM, et al. . CD163+ tumor-associated macrophages correlated with poor prognosis and cancer stem cells in oral squamous cell carcinoma. Biomed Res Int. (2014) 2014:838632. 10.1155/2014/838632 PubMed DOI PMC

Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. (2012) 12:253–68. 10.1038/nri3175 PubMed DOI PMC

Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. (2016) 37:208–20. 10.1016/j.it.2016.01.004 PubMed DOI PMC

Raber P, Ochoa AC, Rodriguez PC. Metabolism of L-arginine by myeloid-derived suppressor cells in cancer: mechanisms of T cell suppression and therapeutic perspectives. Immunol Invest. (2012) 41:614–34. 10.3109/08820139.2012.680634 PubMed DOI PMC

Umansky V, Blattner C, Gebhardt C, Utikal J. The role of Myeloid-Derived Suppressor Cells (MDSC) in cancer progression. Vaccines (Basel). (2016) 4:36 10.3390/vaccines4040036 PubMed DOI PMC

Obermajer N, Muthuswamy R, Odunsi K, Edwards RP, Kalinski P. PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res. (2011) 71:7463–70. 10.1158/0008-5472.CAN-11-2449 PubMed DOI PMC

Lechner MG, Liebertz DJ, Epstein AL. Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. J Immunol. (2010) 185:2273–84. 10.4049/jimmunol.1000901 PubMed DOI PMC

Lang S, Bruderek K, Kaspar C, Höing B, Kanaan O, Dominas N, et al. . Clinical relevance and suppressive capacity of human myeloid-derived suppressor cell subsets. Clin Cancer Res. (2018) 24:4834–44. 10.1158/1078-0432.CCR-17-3726 PubMed DOI

Chikamatsu K, Sakakura K, Toyoda M, Takahashi K, Yamamoto T, Masuyama K. Immunosuppressive activity of CD14+ HLA-DR- cells in squamous cell carcinoma of the head and neck. Cancer Sci. (2012) 103:976–83. 10.1111/j.1349-7006.2012.02248.x PubMed DOI PMC

Vasquez-Dunddel D, Pan F, Zeng Q, Gorbounov M, Albesiano E, Fu J, et al. . STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients. J Clin Invest. (2013) 123:1580–89. 10.1172/JCI60083 PubMed DOI PMC

Greene S, Robbins Y, Mydlarz WK, Huynh AP, Schmitt NC, Friedman J, 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. (2019) 6:1420–31. 10.1158/1078-0432.CCR-19-2625 PubMed DOI PMC

Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev Cancer. (2016) 16:431–46. 10.1038/nrc.2016.52 PubMed DOI

Barros MR, Jr, de Melo CML, Barros M, de Cassia Pereira de Lima R, de Freitas AC, et al. . Activities of stromal and immune cells in HPV-related cancers. J Exp Clin Cancer Res. (2018) 37:137. 10.1186/s13046-018-0802-7 PubMed DOI PMC

Rachidi S, Wallace K, Wrangle JM, Day TA, Alberg AJ, Li Z. Neutrophil-to-lymphocyte ratio and overall survival in all sites of head and neck squamous cell carcinoma. Head Neck. (2016) 38 (Suppl. 1):E1068–74. 10.1002/hed.24159 PubMed DOI PMC

Marchi F, Missale F, Incandela F, Filauro M, Mazzola F, Mora F, et al. . Prognostic significance of peripheral T-cell subsets in laryngeal squamous cell carcinoma. Laryngoscope Investig Otolaryngol. (2019) 4:513–9. 10.1002/lio2.304 PubMed DOI PMC

Huang SH, Waldron JN, Milosevic M, Shen X, Ringash J, Su J, et al. . Prognostic value of pretreatment circulating neutrophils, monocytes, and lymphocytes in oropharyngeal cancer stratified by human papillomavirus status. Cancer. (2015) 121:545–55. 10.1002/cncr.29100 PubMed DOI

Mattavelli D, Lombardi D, Missale F, Calza S, Battocchio S, Paderno A, et al. . Prognostic nomograms in oral squamous cell carcinoma: the negative impact of low neutrophil to lymphocyte ratio. Front Oncol. (2019) 9:339. 10.3389/fonc.2019.00339 PubMed DOI PMC

Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or adaptive immunity? The example of natural killer cells. Science. (2011) 331:44–9. 10.1126/science.1198687 PubMed DOI PMC

Moretta L, Moretta A. Unravelling natural killer cell function: triggering and inhibitory human NK receptors. EMBO J. (2004) 23:255–9. 10.1038/sj.emboj.7600019 PubMed DOI PMC

Bauernhofer T, Kuss I, Henderson B, Baum AS, Whiteside TL. Preferential apoptosis of CD56dim natural killer cell subset in patients with cancer. Eur J Immunol. (2003) 33:119–24. 10.1002/immu.200390014 PubMed DOI

Kloss S, Chambron N, Gardlowski T, Arseniev L, Koch J, Esser R, et al. . Increased sMICA and TGFbeta1 levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells. Oncoimmunology. (2015) 4:e1055993. 10.1080/2162402X.2015.1055993 PubMed DOI PMC

Dhodapkar MV, Steinman RM. Antigen-bearing immature dendritic cells induce peptide-specific CD8(+) regulatory T cells in vivo in humans. Blood. (2002) 100:174–7. 10.1182/blood.V100.1.174 PubMed DOI

Dunn GP, Bruce AT, Sheehan KC, Shankaran V, Uppaluri R, Bui JD, et al. . A critical function for type I interferons in cancer immunoediting. Nat Immunol. (2005) 6:722–9. 10.1038/ni1213 PubMed DOI

Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia A. Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol. (2001) 31:3388–93. 10.1002/1521-4141(200111)31:11<3388::AID-IMMU3388>3.0.CO;2-Q PubMed DOI

Liu YJ. Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell. (2001) 106:259–62. 10.1016/S0092-8674(01)00456-1 PubMed DOI

Hoffmann TK, Muller-Berghaus J, Ferris RL, Johnson JT, Storkus WJ, Whiteside TL. Alterations in the frequency of dendritic cell subsets in the peripheral circulation of patients with squamous cell carcinomas of the head and neck. Clin Cancer Res. (2002) 8:1787–93. PubMed

Reizis B, Bunin A, Ghosh HS, Lewis KL, Sisirak V. Plasmacytoid dendritic cells: recent progress and open questions. Annu Rev Immunol. (2011) 29:163–83. 10.1146/annurev-immunol-031210-101345 PubMed DOI PMC

Villadangos JA, Young L. Antigen-presentation properties of plasmacytoid dendritic cells. Immunity. (2008) 29:352–61. 10.1016/j.immuni.2008.09.002 PubMed DOI

Ito T, Yang M, Wang YH, Lande R, Gregorio J, Perng OA, et al. . Plasmacytoid dendritic cells prime IL-10-producing T regulatory cells by inducible costimulator ligand. J Exp Med. (2007) 204:105–15. 10.1084/jem.20061660 PubMed DOI PMC

Hartmann E, Wollenberg B, Rothenfusser S, Wagner M, Wellisch D, Mack B, et al. . Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res. (2003) 63:6478–87. PubMed

Bruchhage KL, Heinrichs S, Wollenberg B, Pries R. IL-10 in the microenvironment of HNSCC inhibits the CpG ODN induced IFN-alpha secretion of pDCs. Oncol Lett. (2018) 15:3985–90. 10.3892/ol.2018.7772 PubMed DOI PMC

Balermpas P, Rödel F, Rödel C, Krause M, Linge A, Lohaus F, et al. . CD8+ tumour-infiltrating lymphocytes in relation to HPV status and clinical outcome in patients with head and neck cancer after postoperative chemoradiotherapy: a multicentre study of the German cancer consortium radiation oncology group (DKTK-ROG). Int J Cancer. (2016) 138:171–81. 10.1002/ijc.29683 PubMed DOI

Hanna GJ, Liu H, Jones RE, Bacay AF, Lizotte PH, Ivanova EV, et al. . Defining an inflamed tumor immunophenotype in recurrent, metastatic squamous cell carcinoma of the head and neck. Oral Oncol. (2017) 67:61–9. 10.1016/j.oraloncology.2017.02.005 PubMed DOI

Heusinkveld M, Goedemans R, Briet RJ, Gelderblom H, Nortier JW, Gorter A, et al. . Systemic and local human papillomavirus 16-specific T-cell immunity in patients with head and neck cancer. Int J Cancer. (2012) 131:E74–85. 10.1002/ijc.26497 PubMed DOI

Welters MJP, Ma W, Santegoets SJAM, Goedemans R, Ehsan I, Jordanova ES, et al. . Intratumoral HPV16-specific T cells constitute a type i-oriented tumor microenvironment to improve survival in HPV16-driven oropharyngeal cancer. Clin Cancer Res. (2018) 24:634–47. 10.1158/1078-0432.CCR-17-2140 PubMed DOI

Hladíková K, Partlová S, Koucký V, Bouček J, Fonteneau JF, Zábrodský M, et al. . Dysfunction of HPV16-specific CD8+ T cells derived from oropharyngeal tumors is related to the expression of Tim-3 but not PD-1. Oral Oncol. (2018) 82:75–82. 10.1016/j.oraloncology.2018.05.010 PubMed DOI

Russell S, Angell T, Lechner M, Liebertz D, Correa A, Sinha U, et al. . Immune cell infiltration patterns and survival in head and neck squamous cell carcinoma. Head Neck Oncol. (2013) 5:24. PubMed PMC

Zubler RH. Naive and memory B cells in T-cell-dependent and T-independent responses. Springer Semin Immunopathol. (2001) 23:405–19. 10.1007/s281-001-8167-7 PubMed DOI

Largeot A, Pagano G, Gonder S, Moussay E, Paggetti J. The B-side of cancer immunity: the underrated tune. Cells. (2019) 8:449. 10.3390/cells8050449 PubMed DOI PMC

Nelson BH. CD20+ B cells: the other tumor-infiltrating lymphocytes. J Immunol. (2010) 185:4977–82. 10.4049/jimmunol.1001323 PubMed DOI

Nielsen JS, Sahota RA, Milne K, Kost SE, Nesslinger NJ, Watson PH, et al. . CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin Cancer Res. (2012) 18:3281–92. 10.1158/1078-0432.CCR-12-0234 PubMed DOI

Yuen GJ, Demissie E, Pillai S. B lymphocytes and cancer: a love-hate relationship. Trends Cancer. (2016) 2:747–57. 10.1016/j.trecan.2016.10.010 PubMed DOI PMC

Hollern DP, Xu N, Thennavan A, Glodowski C, Garcia-Recio S, Mott KR, et al. . B cells and T follicular helper cells mediate response to checkpoint inhibitors in high mutation burden mouse models of breast cancer. Cell. (2019) 179:1191–206 e1121. 10.1016/j.cell.2019.10.028 PubMed DOI PMC

Wood O, Woo J, Seumois G, Savelyeva N, McCann KJ, Singh D, et al. . Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors. Oncotarget. (2016) 7:56781–97. 10.18632/oncotarget.10788 PubMed DOI PMC

Lechner A, Schlößer HA, Thelen M, Wennhold K, Rothschild SI, Gilles R, et al. . Tumor-associated B cells and humoral immune response in head and neck squamous cell carcinoma. Oncoimmunology. (2019) 8:1535293. 10.1080/2162402X.2018.1535293 PubMed DOI PMC

Smith EM, Pawlita M, Rubenstein LM, Haugen TH, Hamsikova E, Turek LP. Risk factors and survival by HPV-16 E6 and E7 antibody status in human papillomavirus positive head and neck cancer. Int J Cancer. (2010) 127:111–7. 10.1002/ijc.25015 PubMed DOI

Lang Kuhs KA, Kreimer AR, Trivedi S, Holzinger D, Pawlita M, Pfeiffer RM, et al. . Human papillomavirus 16 E6 antibodies are sensitive for human papillomavirus-driven oropharyngeal cancer and are associated with recurrence. Cancer. (2017) 123:4382–90. 10.1002/cncr.30966 PubMed DOI PMC

Chen Z, Malhotra PS, Thomas GR, Ondrey FG, Duffey DC, Smith CW, et al. . Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res. (1999) 5:1369–79. PubMed

Seiwert TY, Cohen EE. Targeting angiogenesis in head and neck cancer. Semin Oncol. (2008) 35:274–85. 10.1053/j.seminoncol.2008.03.005 PubMed DOI

Lapeyre-Prost A, Terme M, Pernot S, Pointet AL, Voron T, Tartour E, et al. . Immunomodulatory activity of VEGF in cancer. Int Rev Cell Mol Biol. (2017) 330:295–342. 10.1016/bs.ircmb.2016.09.007 PubMed DOI

Lathers DM, Achille NJ, Young MR. Incomplete Th2 skewing of cytokines in plasma of patients with squamous cell carcinoma of the head and neck. Hum Immunol. (2003) 64:1160–6. 10.1016/j.humimm.2003.08.024 PubMed DOI

Nakano Y, Kobayashi W, Sugai S, Kimura H, Yagihashi S. Expression of tumor necrosis factor-alpha and interleukin-6 in oral squamous cell carcinoma. Jpn J Cancer Res. (1999) 90:858–66. 10.1111/j.1349-7006.1999.tb00827.x PubMed DOI PMC

Chandler SW, Rassekh CH, Rodman SM, Ducatman BS. Immunohistochemical localization of interleukin-10 in human oral and pharyngeal carcinomas. Laryngoscope. (2002) 112:808–15. 10.1097/00005537-200205000-00008 PubMed DOI

Hamzavi M, Tadbir AA, Rezvani G, Ashraf MJ, Fattahi MJ, Khademi B, et al. . Tissue expression, serum and salivary levels of IL-10 in patients with head and neck squamous cell carcinoma. Asian Pac J Cancer Prev. (2013) 14:1681–5. 10.7314/APJCP.2013.14.3.1681 PubMed DOI

Duffy SA, Taylor JM, Terrell JE, Islam M, Li Y, Fowler KE, et al. . Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer. (2008) 113:750–7. 10.1002/cncr.23615 PubMed DOI

Hirano T. Interleukin 6 and its receptor: ten years later. Int Rev Immunol. (1998) 16:249–84. 10.3109/08830189809042997 PubMed DOI

Park SJ, Nakagawa T, Kitamura H, Atsumi T, Kamon H, Sawa S, et al. . IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. J Immunol. (2004) 173:3844–854. 10.4049/jimmunol.173.6.3844 PubMed DOI

Suzuki S, Mita S, Kamohara H, Sakamoto K, Ishiko T, Ogawa M. IL-6 and IFN-gamma regulation of IL-10 production by human colon carcinoma cells. Int J Oncol. (2001) 18:581–6. 10.3892/ijo.18.3.581 PubMed DOI

Mocellin S, Marincola FM, Young HA. Interleukin-10 and the immune response against cancer: a counterpoint. J Leukoc Biol. (2005) 78:1043–51. 10.1189/jlb.0705358 PubMed DOI

Piva MR, DE Souza LB, Martins-Filho PR, Nonaka CF, DE Santana Santos T, DE Souza Andrade ES, et al. . Role of inflammation in oral carcinogenesis (Part II): CD8, FOXP3, TNF-alpha, TGF-beta and NF-kappaB expression. Oncol Lett. (2013) 5:1909–14. 10.3892/ol.2013.1302 PubMed DOI PMC

Parks RR, Yan SD, Huang CC. Tumor necrosis factor-alpha production in human head and neck squamous cell carcinoma. Laryngoscope. (1994) 104:860–4. 10.1288/00005537-199407000-00015 PubMed DOI

De Guillebon E, Dardenne A, Saldmann A, Séguier S, Tran T, Paolini L, et al. . Beyond the concept of cold and hot tumors for the development of novel predictive biomarkers and the rational design of immunotherapy combination. Int J Cancer. (2020) 147:1509–18. 10.1002/ijc.32889 PubMed DOI

Sallusto F, Lanzavecchia A, Mackay CR. Chemokines and chemokine receptors in T-cell priming and Th1/Th2-mediated responses. Immunol Today. (1998) 19:568–74. 10.1016/S0167-5699(98)01346-2 PubMed DOI

Mizukami Y, Kono K, Kawaguchi Y, Akaike H, Kamimura K, Sugai H, et al. . CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer. Int J Cancer. (2008) 122:2286–93. 10.1002/ijc.23392 PubMed DOI

Semmling V, Lukacs-Kornek V, Thaiss CA, Quast T, Hochheiser K, Panzer U, et al. . Alternative cross-priming through CCL17-CCR4-mediated attraction of CTLs toward NKT cell-licensed DCs. Nat Immunol. (2010) 11:313–20. 10.1038/ni.1848 PubMed DOI

Lin Y, Sharma S, John MS. CCL21 Cancer Immunotherapy. Cancers (Basel). (2014) 6:1098–110. 10.3390/cancers6021098 PubMed DOI PMC

Mehanna H, Robinson M, Hartley A, Kong A, Foran B, Fulton-Lieuw T, et al. . Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Lancet. (2019) 393:51–60. 10.1016/S0140-6736(18)32752-1 PubMed DOI PMC

Gillison ML, Trotti AM, Harris J, Eisbruch A, Harari PM, Adelstein DJ, et al. . Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet. (2019) 393:40–50. 10.1016/S0140-6736(18)32779-X PubMed DOI PMC

Cohen EEW, Bell RB, Bifulco CB, Burtness B, Gillison ML, Harrington KJ, 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. 10.1186/s40425-019-0662-5 PubMed DOI PMC

Shayan G, Srivastava R, Li J, Schmitt N, Kane LP, Ferris RL. Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer. Oncoimmunology. (2017) 6:e1261779. 10.1080/2162402X.2016.1261779 PubMed DOI PMC

Verma V, Shrimali RK, Ahmad S, Dai W, Wang H, Lu S, et al. PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1(+)CD38(hi) cells and anti-PD-1 resistance. Nat Immunol. (2019) 20:1555 10.1038/s41590-019-0519-6 PubMed DOI

Massarelli E, William W, Johnson F, Kies M, Ferrarotto R, Guo M, et al. . Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16-related cancer: a phase 2 clinical trial. JAMA Oncol. (2019) 5:67–73. 10.1001/jamaoncol.2018.4051 PubMed DOI PMC

Petitprez F, de Reyniès A, Keung EZ, Chen TW, Sun CM, Calderaro J, et al. . B cells are associated with survival and immunotherapy response in sarcoma. Nature. (2020) 577:556–60. 10.1038/s41586-019-1906-8 PubMed DOI

Vonderheide RH. CD40 agonist antibodies in cancer immunotherapy. Annu Rev Med. (2020) 71:47–58. 10.1146/annurev-med-062518-045435 PubMed DOI

Tissue contexture determines the pattern and density of tumor-infiltrating immune cells in HPV-associated squamous cell carcinomas of oropharynx and uterine cervix