The Immune Microenvironment in Head and Neck Squamous Cell Carcinoma: on Subsets and Subsites

1.

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(6):394–424. https://doi.org/10.3322/caac.21492.CrossRef

2.

Leemans CR, Snijders PJF, Brakenhoff RH. The molecular landscape of head and neck cancer. Nat Rev Cancer. 2018;18(5):269–82. https://doi.org/10.1038/nrc.2018.11.CrossRefPubMed

3.

Marur S, Forastiere AA. Head and neck cancer: changing epidemiology, diagnosis, and treatment. Mayo Clin Proc. 2008;83(4):489–501. https://doi.org/10.4065/83.4.489.CrossRefPubMed

4.

Moskovitz J, Moy J, Ferris RL. Immunotherapy for head and neck squamous cell carcinoma. Curr Oncol Rep. 2018;20(2):22. https://doi.org/10.1007/s11912-018-0654-5.CrossRefPubMedPubMedCentral

5.

Kotoula V, Chatzopoulos K, Lakis S, Alexopoulou Z, Timotheadou E, Zagouri F, et al. Tumors with high-density tumor infiltrating lymphocytes constitute a favorable entity in breast cancer: a pooled analysis of four prospective adjuvant trials. Oncotarget. 2016;7(4):5074–87. https://doi.org/10.18632/oncotarget.6231.CrossRefPubMed

6.

Geng Y, Shao Y, He W, Hu W, Xu Y, Chen J, et al. Prognostic role of tumor-infiltrating lymphocytes in lung cancer: a meta-analysis. Cell Physiol Biochem. 2015;37(4):1560–71. https://doi.org/10.1159/000438523.CrossRefPubMed

7.

Ferris RL, Hunt JL, Ferrone S. Human leukocyte antigen (HLA) class I defects in head and neck cancer: molecular mechanisms and clinical significance. Immunol Res. 2005;33(2):113–33. https://doi.org/10.1385/IR:33:2:113.CrossRefPubMed

8.

Whiteside TL. Tumor-induced death of immune cells: its mechanisms and consequences. Semin Cancer Biol. 2002;12(1):43–50. https://doi.org/10.1006/scbi.2001.0402.CrossRefPubMed

9.

Ferris RL, Whiteside TL, Ferrone S. Immune escape associated with functional defects in antigen-processing machinery in head and neck cancer. Clin Cancer Res. 2006;12(13):3890–5. https://doi.org/10.1158/1078-0432.CCR-05-2750.CrossRefPubMed

10.

Zandberg DP, Strome SE. The role of the PD-L1:PD-1 pathway in squamous cell carcinoma of the head and neck. Oral Oncol. 2014;50(7):627–32. https://doi.org/10.1016/j.oraloncology.2014.04.003.CrossRefPubMed

11.

Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science (New York, NY). 2011;331(6024):1565–70. https://doi.org/10.1126/science.1203486.CrossRef

12.

• Nguyen N, Bellile E, Thomas D, McHugh J, Rozek L, Virani S, et al. Tumor infiltrating lymphocytes and survival in patients with head and neck squamous cell carcinoma. Head Neck. 2016;38(7):1074–84. https://doi.org/10.1002/hed.24406A comprehensive comparison of immune cell infiltration between HNSCC subsites and HPV-status. CrossRefPubMedPubMedCentral

13.

Costa NL, Goncalves AS, Martins AF, Arantes DA, Silva TA, Batista AC. Characterization of dendritic cells in lip and oral cavity squamous cell carcinoma. J Oral Pathol Med. 2016;45(6):418–24. https://doi.org/10.1111/jop.12380.CrossRefPubMed

14.

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. https://doi.org/10.1016/j.oraloncology.2016.08.016.CrossRefPubMed

15.

Partlova S, Boucek J, Kloudova K, Lukesova E, Zabrodsky 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(1):e965570. https://doi.org/10.4161/21624011.2014.965570.CrossRefPubMedPubMedCentral

16.

Mandal R, Senbabaoglu Y, Desrichard A, Havel JJ, Dalin MG, Riaz N, et al. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight. 2016;1(17):e89829. https://doi.org/10.1172/jci.insight.89829.CrossRefPubMedPubMedCentral

17.

• 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. https://doi.org/10.1016/j.molimm.2018.02.005This study investigates the prognostic significance of various immune subsets for all HNSCC subsites as well as seperately for HPV-negative and -positive HNSCC. CrossRefPubMed

18.

Wang J, Sun H, Zeng Q, Guo XJ, Wang H, Liu HH, et al. HPV-positive status associated with inflamed immune microenvironment and improved response to anti-PD-1 therapy in head and neck squamous cell carcinoma. Sci Rep. 2019;9(1):13404. https://doi.org/10.1038/s41598-019-49771-0.CrossRefPubMedPubMedCentral

19.

Masucci MT, Minopoli M, Carriero MV. Tumor associated neutrophils. Their role in tumorigenesis, metastasis, prognosis and therapy. Front Oncol. 2019;9:1146. https://doi.org/10.3389/fonc.2019.01146.CrossRefPubMedPubMedCentral

20.

Zhang X, Zhang W, Yuan X, Fu M, Qian H, Xu W. Neutrophils in cancer development and progression: roles, mechanisms, and implications (review). Int J Oncol. 2016;49(3):857–67. https://doi.org/10.3892/ijo.2016.3616.CrossRefPubMed

21.

Trellakis S, Bruderek K, Dumitru CA, Gholaman H, Gu X, Bankfalvi A, et al. Polymorphonuclear granulocytes in human head and neck cancer: enhanced inflammatory activity, modulation by cancer cells and expansion in advanced disease. Int J Cancer. 2011;129(9):2183–93. https://doi.org/10.1002/ijc.25892.CrossRefPubMed

22.

Dumitru CA, Bankfalvi A, Gu X, Eberhardt WE, Zeidler R, Lang S, et al. Neutrophils activate tumoral CORTACTIN to enhance progression of orohypopharynx carcinoma. Front Immunol. 2013;4:33. https://doi.org/10.3389/fimmu.2013.00033.CrossRefPubMedPubMedCentral

23.

Moy JD, Moskovitz JM, Ferris RL. Biological mechanisms of immune escape and implications for immunotherapy in head and neck squamous cell carcinoma. Eur J Cancer. 2017;76:152–66. https://doi.org/10.1016/j.ejca.2016.12.035.CrossRefPubMedPubMedCentral

24.

Concha-Benavente F, Kansy B, Moskovitz J, Moy J, Chandran U, Ferris RL. PD-L1 mediates dysfunction in activated PD-1(+) NK cells in head and neck cancer patients. Cancer Immunol Res. 2018;6(12):1548–60. https://doi.org/10.1158/2326-6066.Cir-18-0062.CrossRefPubMedPubMedCentral

25.

Wagner S, Wittekindt C, Reuschenbach M, Hennig B, Thevarajah M, Wurdemann 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(9):2263–73. https://doi.org/10.1002/ijc.29962.CrossRefPubMed

26.

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(9):1007–10. https://doi.org/10.1001/archotol.1991.01870210079015.CrossRefPubMed

27.

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(6):641–6. https://doi.org/10.1001/archotol.124.6.641.CrossRefPubMed

28.

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(11):2136–47.CrossRef

29.

Yilmaz T, Gedikoglu G, Celik A, Onerci M, Turan E. Prognostic significance of Langerhans cell infiltration in cancer of the larynx. Otolaryngol Head Neck Surg. 2005;132(2):309–16. https://doi.org/10.1016/j.otohns.2004.04.018.CrossRefPubMed

30.

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(3):E85–93. https://doi.org/10.1002/ijc.27728.CrossRefPubMed

31.

Jardim JF, Gondak R, Galvis MM, Pinto CAL, Kowalski LP. A decreased peritumoral CD1a+ cell number predicts a worse prognosis in oral squamous cell carcinoma. Histopathology. 2018;72(6):905–13. https://doi.org/10.1111/his.13415.CrossRefPubMed

32.

Karpathiou G, Casteillo F, Giroult JB, Forest F, Fournel P, Monaya A, et al. Prognostic impact of immune microenvironment in laryngeal and pharyngeal squamous cell carcinoma: immune cell subtypes, immuno-suppressive pathways and clinicopathologic characteristics. Oncotarget. 2017;8(12):19310–22. https://doi.org/10.18632/oncotarget.14242.CrossRefPubMed

33.

Chang CS, Chang JH, Hsu NC, Lin HY, Chung CY. Expression of CD80 and CD86 costimulatory molecules are potential markers for better survival in nasopharyngeal carcinoma. BMC Cancer. 2007;7:88. https://doi.org/10.1186/1471-2407-7-88.CrossRefPubMedPubMedCentral

34.

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(1):145–52. https://doi.org/10.1016/j.canlet.2007.04.003.CrossRefPubMedPubMedCentral

35.

Karakok M, Bayazit YA, Ucak R, Ozer E, Kanlikama M, Mumbuc S, et al. Langerhans cell related inflammatory reaction in laryngeal squamous cell carcinoma. Auris Nasus Larynx. 2003;30(1):81–4. https://doi.org/10.1016/s0385-8146(02)00025-1.CrossRefPubMed

36.

Gomes JO, de Vasconcelos CM, Fonseca FP, Gondak RO, Lopes MA, Vargas PA. CD1a+ and CD83+ Langerhans cells are reduced in lower lip squamous cell carcinoma. J Oral Pathol Med. 2016;45(6):433–9. https://doi.org/10.1111/jop.12389.CrossRefPubMed

37.

Hilly O, Strenov Y, Rath-Wolfson L, Hod R, Shkedy Y, Mizrachi A, et al. The predictive value of dendritic cells in early squamous cell carcinoma of the tongue. Pathol Res Pract. 2016;212(12):1138–43. https://doi.org/10.1016/j.prp.2016.09.011.CrossRefPubMed

38.

Matthews K, Leong CM, Baxter L, Inglis E, Yun K, Backstrom BT, et al. Depletion of Langerhans cells in human papillomavirus type 16-infected skin is associated with E6-mediated down regulation of E-cadherin. J Virol. 2003;77(15):8378–85. https://doi.org/10.1128/jvi.77.15.8378-8385.2003.CrossRefPubMedPubMedCentral

39.

Guess JC, McCance DJ. Decreased migration of Langerhans precursor-like cells in response to human keratinocytes expressing human papillomavirus type 16 E6/E7 is related to reduced macrophage inflammatory protein-3alpha production. J Virol. 2005;79(23):14852–62. https://doi.org/10.1128/jvi.79.23.14852-14862.2005.CrossRefPubMedPubMedCentral

40.

Pereira KM, Soares RC, Oliveira MC, Pinto LP, Costa AL. Immunohistochemical staining of Langerhans cells in HPV-positive and HPV-negative cases of oral squamous cells carcinoma. J Appl Oral Sci. 2011;19(4):378–83. https://doi.org/10.1590/s1678-77572011005000013.CrossRefPubMedPubMedCentral

41.

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(19):6478–87.PubMed

42.

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. https://doi.org/10.1016/j.archoralbio.2017.02.012.CrossRefPubMed

43.

Pellicioli ACA, Bingle L, Farthing P, Lopes MA, Martins MD, Vargas PA. Immunosurveillance profile of oral squamous cell carcinoma and oral epithelial dysplasia through dendritic and T-cell analysis. J Oral Pathol Med. 2017;46(10):928–33. https://doi.org/10.1111/jop.12597.CrossRefPubMed

44.

Gilliet M, Cao W, Liu YJ. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol. 2008;8(8):594–606. https://doi.org/10.1038/nri2358.CrossRefPubMed

45.

Lombardi VC, Khaiboullina SF, Rizvanov AA. Plasmacytoid dendritic cells, a role in neoplastic prevention and progression. Eur J Clin Investig. 2015;45(Suppl 1):1–8. https://doi.org/10.1111/eci.12363.CrossRef

46.

Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014;6:13. https://doi.org/10.12703/p6-13.CrossRefPubMedPubMedCentral

47.

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. https://doi.org/10.1155/2010/701657.CrossRefPubMed

48.

Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14(7):399–416. https://doi.org/10.1038/nrclinonc.2016.217.CrossRefPubMedPubMedCentral

49.

Marcus B, Arenberg D, Lee J, Kleer C, Chepeha DB, Schmalbach CE, et al. Prognostic factors in oral cavity and oropharyngeal squamous cell carcinoma. Cancer. 2004;101(12):2779–87. https://doi.org/10.1002/cncr.20701.CrossRefPubMed

50.

Lu CF, Huang CS, Tjiu JW, Chiang CP. Infiltrating macrophage count: a significant predictor for the progression and prognosis of oral squamous cell carcinomas in Taiwan. Head Neck. 2010;32(1):18–25. https://doi.org/10.1002/hed.21138.CrossRefPubMed

51.

Costa NL, Valadares MC, Souza PP, Mendonca 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(3):216–23. https://doi.org/10.1016/j.oraloncology.2012.09.012.CrossRefPubMed

52.

Seminerio I, Kindt N, Descamps G, Bellier J, Lechien JR, Mat Q, et al. High infiltration of CD68+ macrophages is associated with poor prognoses of head and neck squamous cell carcinoma patients and is influenced by human papillomavirus. Oncotarget. 2018;9(13):11046–59. https://doi.org/10.18632/oncotarget.24306.CrossRefPubMedPubMedCentral

53.

Yu GT, Bu LL, Huang CF, Zhang WF, Chen WJ, Gutkind JS, et al. PD-1 blockade attenuates immunosuppressive myeloid cells due to inhibition of CD47/SIRPalpha axis in HPV negative head and neck squamous cell carcinoma. Oncotarget. 2015;6(39):42067–80. https://doi.org/10.18632/oncotarget.5955.CrossRefPubMedPubMedCentral

54.

Ni YH, Ding L, Huang XF, Dong YC, Hu QG, Hou YY. Microlocalization of CD68+ tumor-associated macrophages in tumor stroma correlated with poor clinical outcomes in oral squamous cell carcinoma patients. Tumour Biol. 2015;36(7):5291–8. https://doi.org/10.1007/s13277-015-3189-5.CrossRefPubMed

55.

Liu SY, Chang LC, Pan LF, Hung YJ, Lee CH, Shieh YS. Clinicopathologic significance of tumor cell-lined vessel and microenvironment in oral squamous cell carcinoma. Oral Oncol. 2008;44(3):277–85. https://doi.org/10.1016/j.oraloncology.2007.02.007.CrossRefPubMed

56.

Wolf GT, Chepeha DB, Bellile E, Nguyen A, Thomas D, McHugh J. Tumor infiltrating lymphocytes (TIL) and prognosis in oral cavity squamous carcinoma: a preliminary study. Oral Oncol. 2015;51(1):90–5. https://doi.org/10.1016/j.oraloncology.2014.09.006.CrossRefPubMed

57.

Lee YS, Park JY, Cho KJ, Kim SB, Lee SW, Choi SH, et al. Composition of inflammatory cells regulating the response to concurrent chemoradiation therapy for HPV (+) tonsil cancer. Oral Oncol. 2015;51(12):1113–9. https://doi.org/10.1016/j.oraloncology.2015.10.001.CrossRefPubMed

58.

Hu Y, He MY, Zhu LF, Yang CC, Zhou ML, Wang Q, et al. Tumor-associated macrophages correlate with the clinicopathological features and poor outcomes via inducing epithelial to mesenchymal transition in oral squamous cell carcinoma. J Exp Clin Cancer Res. 2016;35:12. https://doi.org/10.1186/s13046-015-0281-z.CrossRefPubMedPubMedCentral

59.

Wansom D, Light E, Thomas D, Worden F, Prince M, Urba S, et al. Infiltrating lymphocytes and human papillomavirus-16--associated oropharyngeal cancer. Laryngoscope. 2012;122(1):121–7. https://doi.org/10.1002/lary.22133.CrossRefPubMedPubMedCentral

60.

Oguejiofor K, Galletta-Williams H, Dovedi SJ, Roberts DL, Stern PL, West CM. Distinct patterns of infiltrating CD8+ T cells in HPV+ and CD68 macrophages in HPV- oropharyngeal squamous cell carcinomas are associated with better clinical outcome but PD-L1 expression is not prognostic. Oncotarget. 2017;8(9):14416–27. https://doi.org/10.18632/oncotarget.14796.CrossRefPubMedPubMedCentral

61.

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. https://doi.org/10.1155/2014/838632.CrossRefPubMedPubMedCentral

62.

Fujii N, Shomori K, Shiomi T, Nakabayashi M, Takeda C, Ryoke K, et al. Cancer-associated fibroblasts and CD163-positive macrophages in oral squamous cell carcinoma: their clinicopathological and prognostic significance. J Oral Pathol Med. 2012;41(6):444–51. https://doi.org/10.1111/j.1600-0714.2012.01127.x.CrossRefPubMed

63.

Verreck FA, de Boer T, Langenberg DM, van der Zanden L, Ottenhoff TH. Phenotypic and functional profiling of human proinflammatory type-1 and anti-inflammatory type-2 macrophages in response to microbial antigens and IFN-gamma- and CD40L-mediated costimulation. J Leukoc Biol. 2006;79(2):285–93. https://doi.org/10.1189/jlb.0105015.CrossRefPubMed

64.

Chiu KC, Lee CH, Liu SY, Chou YT, Huang RY, Huang SM, et al. Polarization of tumor-associated macrophages and Gas6/Axl signaling in oral squamous cell carcinoma. Oral Oncol. 2015;51(7):683–9. https://doi.org/10.1016/j.oraloncology.2015.04.004.CrossRefPubMed

65.

Chang KP, Kao HK, Yen TC, Chang YL, Liang Y, Liu SC, et al. Overexpression of macrophage inflammatory protein-3alpha in oral cavity squamous cell carcinoma is associated with nodal metastasis. Oral Oncol. 2011;47(2):108–13. https://doi.org/10.1016/j.oraloncology.2010.11.012.CrossRefPubMed

66.

Pirila E, Vayrynen O, Sundquist E, Pakkila K, Nyberg P, Nurmenniemi S, et al. Macrophages modulate migration and invasion of human tongue squamous cell carcinoma. PLoS One. 2015;10(3):e0120895. https://doi.org/10.1371/journal.pone.0120895.CrossRefPubMedPubMedCentral

67.

Matsuoka Y, Yoshida R, Nakayama H, Nagata M, Hirosue A, Tanaka T, et al. The tumour stromal features are associated with resistance to 5-FU-based chemoradiotherapy and a poor prognosis in patients with oral squamous cell carcinoma. Apmis. 2015;123(3):205–14. https://doi.org/10.1111/apm.12344.CrossRefPubMed

68.

Wang S, Sun M, Gu C, Wang X, Chen D, Zhao E, et al. Expression of CD163, interleukin-10, and interferon-gamma in oral squamous cell carcinoma: mutual relationships and prognostic implications. Eur J Oral Sci. 2014;122(3):202–9. https://doi.org/10.1111/eos.12131.CrossRefPubMed

69.

Balermpas P, Rodel F, Liberz R, Oppermann J, Wagenblast J, Ghanaati S, et al. Head and neck cancer relapse after chemoradiotherapy correlates with CD163+ macrophages in primary tumour and CD11b+ myeloid cells in recurrences. Br J Cancer. 2014;111(8):1509–18. https://doi.org/10.1038/bjc.2014.446.CrossRefPubMedPubMedCentral

70.

Schneider K, Marbaix E, Bouzin C, Hamoir M, Mahy P, Bol V, et al. Immune cell infiltration in head and neck squamous cell carcinoma and patient outcome: a retrospective study. Acta Oncol. 2018;57(9):1165–72. https://doi.org/10.1080/0284186X.2018.1445287.CrossRefPubMed

71.

Ou D, Adam J, Garberis I, Blanchard P, Nguyen F, Levy A, et al. Influence of tumor-associated macrophages and HLA class I expression according to HPV status in head and neck cancer patients receiving chemo/bioradiotherapy. Radiother Oncol. 2019;130:89–96. https://doi.org/10.1016/j.radonc.2018.08.013.CrossRefPubMed

72.

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(10):e1498439. https://doi.org/10.1080/2162402X.2018.1498439.CrossRefPubMedPubMedCentral

73.

Saloura V, Izumchenko E, Zuo Z, Bao R, Korzinkin M, Ozerov I, et al. Immune profiles in primary squamous cell carcinoma of the head and neck. Oral Oncol. 2019;96:77–88. https://doi.org/10.1016/j.oraloncology.2019.06.032.CrossRefPubMed

74.

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(3):24.PubMedPubMedCentral

75.

Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol. 2009;182(8):4499–506. https://doi.org/10.4049/jimmunol.0802740.CrossRefPubMedPubMedCentral

76.

Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2001;166(1):678–89. https://doi.org/10.4049/jimmunol.166.1.678.CrossRefPubMed

77.

Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol. 2007;179(2):977–83. https://doi.org/10.4049/jimmunol.179.2.977.CrossRefPubMed

78.

Bu LL, Yu GT, Deng WW, Mao L, Liu JF, Ma SR, et al. Targeting STAT3 signaling reduces immunosuppressive myeloid cells in head and neck squamous cell carcinoma. Oncoimmunology. 2016;5(5):e1130206. https://doi.org/10.1080/2162402x.2015.1130206.CrossRefPubMedPubMedCentral

79.

Ma X, Sheng S, Wu J, Jiang Y, Gao X, Cen X, et al. LncRNAs as an intermediate in HPV16 promoting myeloid-derived suppressor cell recruitment of head and neck squamous cell carcinoma. Oncotarget. 2017;8(26):42061–75. https://doi.org/10.18632/oncotarget.14939.CrossRefPubMedPubMedCentral

80.

Zhang N, Bevan MJ. CD8(+) T cells: foot soldiers of the immune system. Immunity. 2011;35(2):161–8. https://doi.org/10.1016/j.immuni.2011.07.010.CrossRefPubMedPubMedCentral

81.

Balermpas P, Michel Y, Wagenblast J, Seitz O, Weiss C, Rodel F, et al. Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancer. Br J Cancer. 2014;110(2):501–9. https://doi.org/10.1038/bjc.2013.640.CrossRefPubMed

82.

Balermpas P, Rodel F, Rodel 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(1):171–81. https://doi.org/10.1002/ijc.29683.CrossRefPubMed

83.

Kim HR, Ha SJ, Hong MH, Heo SJ, Koh YW, Choi EC, et al. PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for head and neck cancer patients. Sci Rep. 2016;6:36956. https://doi.org/10.1038/srep36956.CrossRefPubMedPubMedCentral

84.

de Ruiter EJ, Ooft ML, Devriese LA, Willems SM. 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(11):e1356148. https://doi.org/10.1080/2162402X.2017.1356148.CrossRefPubMedPubMedCentral

85.

Spector ME, Bellile E, Amlani L, Zarins K, Smith J, Brenner JC, et al. Prognostic value of tumor-infiltrating lymphocytes in head and neck squamous cell carcinoma. JAMA Otolaryngol Head Neck Surg. 2019. https://doi.org/10.1001/jamaoto.2019.2427.

86.

Fang J, Li X, Ma D, Liu X, Chen Y, Wang Y, et al. Prognostic significance of tumor infiltrating immune cells in oral squamous cell carcinoma. BMC Cancer. 2017;17(1):375. https://doi.org/10.1186/s12885-017-3317-2.CrossRefPubMedPubMedCentral

87.

Zhou C, Wu Y, Jiang L, Li Z, Diao P, Wang D, et al. Density and location of CD3(+) and CD8(+) tumor-infiltrating lymphocytes correlate with prognosis of oral squamous cell carcinoma. J Oral Pathol Med. 2018;47(4):359–67. https://doi.org/10.1111/jop.12698.CrossRefPubMed

88.

Stasikowska-Kanicka O, Wagrowska-Danilewicz M, Danilewicz M. Immunohistochemical analysis of Foxp3(+), CD4(+), CD8(+) cell infiltrates and PD-L1 in oral squamous cell carcinoma. Pathol Oncol Res. 2018;24(3):497–505. https://doi.org/10.1007/s12253-017-0270-y.CrossRefPubMed

89.

Watanabe Y, Katou F, Ohtani H, Nakayama T, Yoshie O, Hashimoto K. Tumor-infiltrating lymphocytes, particularly the balance between CD8(+) T cells and CCR4(+) regulatory T cells, affect the survival of patients with oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;109(5):744–52. https://doi.org/10.1016/j.tripleo.2009.12.015.CrossRefPubMed

90.

• Feng Z, Bethmann D, Kappler M, Ballesteros-Merino C, Eckert A, Bell RB, et al. Multiparametric immune profiling in HPV- oral squamous cell cancer. JCI Insight. 2017;2(14). https://doi.org/10.1172/jci.insight.93652This study, performing multiplex IHC in a large cohort of HPV-unrelated OCSCC, showed that the spatial distance between CD8+ TIL and Treg at the tumor invasive margin was of importance for prognosis.

91.

Wirsing AM, Ervik IK, Seppola M, Uhlin-Hansen L, Steigen SE, Hadler-Olsen E. Presence of high-endothelial venules correlates with a favorable immune microenvironment in oral squamous cell carcinoma. Mod Pathol. 2018;31(6):910–22. https://doi.org/10.1038/s41379-018-0019-5.CrossRefPubMed

92.

Ahn H, Yang JM, Kim H, Chung JH, Ahn SH, Jeong WJ, et al. Clinicopathologic implications of the miR-197/PD-L1 axis in oral squamous cell carcinoma. Oncotarget. 2017;8(39):66178–94. https://doi.org/10.18632/oncotarget.19842.CrossRefPubMedPubMedCentral

93.

Kogashiwa Y, Yasuda M, Sakurai H, Nakahira M, Sano Y, Gonda K, et al. PD-L1 expression confers better prognosis in locally advanced oral squamous cell carcinoma. Anticancer Res. 2017;37(3):1417–24. https://doi.org/10.21873/anticanres.11465.CrossRefPubMed

94.

Mattox AK, Lee J, Westra WH, Pierce RH, Ghossein R, Faquin WC, et al. PD-1 expression in head and neck squamous cell carcinomas derives primarily from functionally anergic CD4(+) TILs in the presence of PD-L1(+) TAMs. Cancer Res. 2017;77(22):6365–74. https://doi.org/10.1158/0008-5472.Can-16-3453.CrossRefPubMedPubMedCentral

95.

Wu L, Deng WW, Huang CF, Bu LL, Yu GT, Mao L, et al. Expression of VISTA correlated with immunosuppression and synergized with CD8 to predict survival in human oral squamous cell carcinoma. Cancer Immunol Immunother. 2017;66(5):627–36. https://doi.org/10.1007/s00262-017-1968-0.CrossRefPubMed

96.

Dayan D, Salo T, Salo S, Nyberg P, Nurmenniemi S, Costea DE, et al. Molecular crosstalk between cancer cells and tumor microenvironment components suggests potential targets for new therapeutic approaches in mobile tongue cancer. Cancer Med. 2012;1(2):128–40. https://doi.org/10.1002/cam4.24.CrossRefPubMedPubMedCentral

97.

Boxberg M, Leising L, Steiger K, Jesinghaus M, Alkhamas A, Mielke M, et al. Composition and clinical impact of the immunologic tumor microenvironment in oral squamous cell carcinoma. J Immunol. 2019;202(1):278–91. https://doi.org/10.4049/jimmunol.1800242.CrossRefPubMed

98.

Chen YP, Wang YQ, Lv JW, Li YQ, Chua MLK, Le QT, 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(1):68–75. https://doi.org/10.1093/annonc/mdy470.CrossRefPubMed

99.

Ni YH, Zhang XX, Lu ZY, Huang XF, Wang ZY, Yang Y, et al. Tumor-infiltrating CD1a(+) DCs and CD8(+)/FoxP3(+) ratios served as predictors for clinical outcomes in tongue squamous cell carcinoma patients. Pathol Oncol Res. 2019. https://doi.org/10.1007/s12253-019-00701-5.

100.

Huang Z, Xie N, Liu H, Wan Y, Zhu Y, Zhang M, et al. The prognostic role of tumour-infiltrating lymphocytes in oral squamous cell carcinoma: a meta-analysis. J Oral Pathol Med. 2019;48(9):788–98. https://doi.org/10.1111/jop.12927.CrossRefPubMed

101.

Hadler-Olsen E, Wirsing AM. Tissue-infiltrating immune cells as prognostic markers in oral squamous cell carcinoma: a systematic review and meta-analysis. Br J Cancer. 2019;120(7):714–27. https://doi.org/10.1038/s41416-019-0409-6.CrossRefPubMedPubMedCentral

102.

Nordfors C, Grun N, Tertipis N, Ahrlund-Richter A, Haeggblom L, Sivars L, 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(11):2522–30. https://doi.org/10.1016/j.ejca.2013.03.019.CrossRefPubMed

103.

Nasman A, Romanitan M, Nordfors C, Grun 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(6):e38711. https://doi.org/10.1371/journal.pone.0038711.CrossRefPubMedPubMedCentral

104.

Jung AC, Guihard S, Krugell S, Ledrappier S, Brochot A, Dalstein V, et al. CD8-alpha T-cell infiltration in human papillomavirus-related oropharyngeal carcinoma correlates with improved patient prognosis. Int J Cancer. 2013;132(2):E26–36. https://doi.org/10.1002/ijc.27776.CrossRefPubMed

105.

Poropatich K, Hernandez D, Fontanarosa J, Brown K, Woloschak G, Paintal A, et al. Peritumoral cuffing by T-cell tumor-infiltrating lymphocytes distinguishes HPV-related oropharyngeal squamous cell carcinoma from oral cavity squamous cell carcinoma. J Oral Pathol Med. 2017;46(10):972–8. https://doi.org/10.1111/jop.12605.CrossRefPubMed

106.

Oguejiofor K, Hall J, Slater C, Betts G, Hall G, Slevin N, et al. Stromal infiltration of CD8 T cells is associated with improved clinical outcome in HPV-positive oropharyngeal squamous carcinoma. Br J Cancer. 2015;113(6):886–93. https://doi.org/10.1038/bjc.2015.277.CrossRefPubMedPubMedCentral

107.

De Meulenaere A, Vermassen T, Aspeslagh S, Deron P, Duprez F, Laukens D, et al. Tumor PD-L1 status and CD8(+) tumor-infiltrating T cells: markers of improved prognosis in oropharyngeal cancer. Oncotarget. 2017;8(46):80443–52. https://doi.org/10.18632/oncotarget.19045.CrossRefPubMedPubMedCentral

108.

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(3):295–304. https://doi.org/10.1158/2326-6066.Cir-17-0299.CrossRefPubMed

109.

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(2):489–500. https://doi.org/10.1038/bjc.2013.639.CrossRefPubMed

110.

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(1):128–38. https://doi.org/10.1158/0008-5472.CAN-12-2606.CrossRefPubMed

111.

Hoesli R, Birkeland AC, Rosko AJ, Issa M, Chow KL, Michmerhuizen NL, et al. Proportion of CD4 and CD8 tumor infiltrating lymphocytes predicts survival in persistent/recurrent laryngeal squamous cell carcinoma. Oral Oncol. 2018;77:83–9. https://doi.org/10.1016/j.oraloncology.2017.12.003.CrossRefPubMed

112.

Chatzopoulos K, Kotoula V, Manoussou K, Markou K, Vlachtsis K, Angouridakis N, et al. Tumor infiltrating lymphocytes and CD8+ T cell subsets as prognostic markers in patients with surgically treated laryngeal squamous cell carcinoma. Head Neck Pathol. 2019. https://doi.org/10.1007/s12105-019-01101-6.

113.

Kim HJ, Cantor H. CD4 T-cell subsets and tumor immunity: the helpful and the not-so-helpful. Cancer Immunol Res. 2014;2(2):91–8. https://doi.org/10.1158/2326-6066.CIR-13-0216.CrossRefPubMed

114.

Loose D, Signore A, Bonanno E, Vermeersch H, Dierckx R, Deron P, et al. Prognostic value of CD25 expression on lymphocytes and tumor cells in squamous-cell carcinoma of the head and neck. Cancer Biother Radiopharm. 2008;23(1):25–33. https://doi.org/10.1089/cbr.2007.0373.CrossRefPubMed

115.

Moreira G, Fulgencio LB, De Mendonça EF, Leles CR, Batista AC, da Silva TA. T regulatory cell markers in oral squamous cell carcinoma: relationship with survival and tumor aggressiveness. Oncol Lett. 2010;1(1):127–32. https://doi.org/10.3892/ol_00000023.CrossRefPubMedPubMedCentral

116.

• Cillo AR, Kurten CHL, Tabib T, Qi Z, Onkar S, Wang T, et al. Immune landscape of viral- and carcinogen-driven head and neck Cancer. Immunity. 2019. https://doi.org/10.1016/j.immuni.2019.11.014In this recent work scRNAseq was used to identify tumor-infiltrating immune cell subsets more pronounced in HPV-related HNSCC than HPV-unrelated HNSCC.

117.

Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490–500. https://doi.org/10.1038/nri2785.CrossRefPubMed

118.

Shang B, Liu Y, Jiang SJ, Liu Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep. 2015;5:15179. https://doi.org/10.1038/srep15179.CrossRefPubMedPubMedCentral

119.

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(2):465–72. https://doi.org/10.1158/1078-0432.CCR-05-1886.CrossRefPubMed

120.

Seminerio I, Descamps G, Dupont S, de Marrez L, Laigle JA, Lechien JR, et al. Infiltration of FoxP3+ regulatory T cells is a strong and independent prognostic factor in head and neck squamous cell carcinoma. Cancers (Basel). 2019;11(2). https://doi.org/10.3390/cancers11020227.

121.

Liang YJ, Liu HC, Su YX, Zhang TH, Chu M, Liang LZ, et al. Foxp3 expressed by tongue squamous cell carcinoma cells correlates with clinicopathologic features and overall survival in tongue squamous cell carcinoma patients. Oral Oncol. 2011;47(7):566–70. https://doi.org/10.1016/j.oraloncology.2011.04.017.CrossRefPubMed

122.

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. https://doi.org/10.1016/j.oraloncology.2015.11.003.CrossRefPubMed

123.

Song JJ, Zhao SJ, Fang J, Ma D, Liu XQ, Chen XB, et al. Foxp3 overexpression in tumor cells predicts poor survival in oral squamous cell carcinoma. BMC Cancer. 2016;16:530. https://doi.org/10.1186/s12885-016-2419-6.CrossRefPubMedPubMedCentral

124.

Chen WY, Wu CT, Wang CW, Lan KH, Liang HK, Huang BS, et al. Prognostic significance of tumor-infiltrating lymphocytes in patients with operable tongue cancer. Radiat Oncol. 2018;13(1):157. https://doi.org/10.1186/s13014-018-1099-6.CrossRefPubMedPubMedCentral

125.

Fujita Y, Okamoto M, Goda H, Tano T, Nakashiro K, Sugita A, et al. Prognostic significance of interleukin-8 and CD163-positive cell-infiltration in tumor tissues in patients with oral squamous cell carcinoma. PLoS One. 2014;9(12):e110378. https://doi.org/10.1371/journal.pone.0110378.CrossRefPubMedPubMedCentral

126.

Echarti A, Hecht M, Buttner-Herold M, Haderlein M, Hartmann A, Fietkau R, et al. CD8+ and regulatory T cells differentiate tumor immune phenotypes and predict survival in locally advanced head and neck cancer. Cancers (Basel). 2019;11(9). https://doi.org/10.3390/cancers11091398.

127.

Magg T, Mannert J, Ellwart JW, Schmid I, Albert MH. Subcellular localization of FOXP3 in human regulatory and nonregulatory T cells. Eur J Immunol. 2012;42(6):1627–38. https://doi.org/10.1002/eji.201141838.CrossRefPubMed

128.

Chen C, Rowell EA, Thomas RM, Hancock WW, Wells AD. Transcriptional regulation by Foxp3 is associated with direct promoter occupancy and modulation of histone acetylation. J Biol Chem. 2006;281(48):36828–34. https://doi.org/10.1074/jbc.M608848200.CrossRefPubMed

129.

Weed DT, Walker G, De La Fuente AC, Nazarian R, Vella JL, Gomez-Fernandez CR, et al. FOXP3 subcellular localization predicts recurrence in oral squamous cell carcinoma. PLoS One. 2013;8(8):e71908. https://doi.org/10.1371/journal.pone.0071908.CrossRefPubMedPubMedCentral

130.

Kindt N, Descamps G, Seminerio I, Bellier J, Lechien JR, Mat Q, et al. High stromal Foxp3-positive T cell number combined to tumor stage improved prognosis in head and neck squamous cell carcinoma. Oral Oncol. 2017;67:183–91. https://doi.org/10.1016/j.oraloncology.2017.02.023.CrossRefPubMed

131.

Park K, Cho KJ, Lee M, Yoon DH, Kim SB. Importance of FOXP3 in prognosis and its relationship with p16 in tonsillar squamous cell carcinoma. Anticancer Res. 2013;33(12):5667–73.PubMed

132.

Weller MA, Ward MC, Berriochoa C, Reddy CA, Trosman S, Greskovich JF, et al. Predictors of distant metastasis in human papillomavirus-associated oropharyngeal cancer. Head Neck. 2017;39(5):940–6. https://doi.org/10.1002/hed.24711.CrossRefPubMed

133.

Punt S, Dronkers EA, Welters MJ, Goedemans R, Koljenovic S, Bloemena E, et al. A beneficial tumor microenvironment in oropharyngeal squamous cell carcinoma is characterized by a high T cell and low IL-17(+) cell frequency. Cancer Immunol Immunother. 2016;65(4):393–403. https://doi.org/10.1007/s00262-016-1805-x.CrossRefPubMedPubMedCentral

134.

Krupar R, Robold K, Gaag D, Spanier G, Kreutz M, Renner K, et al. Immunologic and metabolic characteristics of HPV-negative and HPV-positive head and neck squamous cell carcinomas are strikingly different. Virchows Arch. 2014;465(3):299–312. https://doi.org/10.1007/s00428-014-1630-6.CrossRefPubMed

135.

Lechner A, Schlosser H, Rothschild SI, Thelen M, Reuter S, Zentis P, et al. Characterization of tumor-associated T-lymphocyte subsets and immune checkpoint molecules in head and neck squamous cell carcinoma. Oncotarget. 2017;8(27):44418–33. https://doi.org/10.18632/oncotarget.17901.CrossRefPubMedPubMedCentral

136.

Flynn NJ, Somasundaram R, Arnold KM, Sims-Mourtada J. The multifaceted roles of B cells in solid tumors: emerging treatment opportunities. Target Oncol. 2017;12(2):139–52. https://doi.org/10.1007/s11523-017-0481-x.CrossRefPubMed

137.

Deola S, Panelli MC, Maric D, Selleri S, Dmitrieva NI, Voss CY, et al. Helper B cells promote cytotoxic T cell survival and proliferation independently of antigen presentation through CD27/CD70 interactions. J Immunol. 2008;180(3):1362–72. https://doi.org/10.4049/jimmunol.180.3.1362.CrossRefPubMed

138.

Schwartz M, Zhang Y, Rosenblatt JD. B cell regulation of the anti-tumor response and role in carcinogenesis. J Immunother Cancer. 2016;4:40. https://doi.org/10.1186/s40425-016-0145-x.CrossRefPubMedPubMedCentral

139.

• Lechner A, Schlosser 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(3):1535293. https://doi.org/10.1080/2162402X.2018.1535293First study reporting on extensive flow cytometric phenotyping of tumor-infiltrating B cells using a small set of HNSCC subsites. CrossRefPubMedPubMedCentral

140.

Wood O, Clarke J, Woo J, Mirza AH, Woelk CH, Thomas GJ, et al. Head and neck squamous cell carcinomas are characterized by a stable immune signature within the primary tumor over time and space. Clin Cancer Res. 2017;23(24):7641–9. https://doi.org/10.1158/1078-0432.CCR-17-0373.CrossRefPubMed

141.

Hladikova K, Koucky V, Boucek 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(1):261. https://doi.org/10.1186/s40425-019-0726-6.CrossRefPubMedPubMedCentral

142.

Pretscher D, Distel LV, Grabenbauer GG, Wittlinger M, Buettner M, Niedobitek G. Distribution of immune cells in head and neck cancer: CD8+ T-cells and CD20+ B-cells in metastatic lymph nodes are associated with favourable outcome in patients with oro- and hypopharyngeal carcinoma. BMC Cancer. 2009;9:292. https://doi.org/10.1186/1471-2407-9-292.CrossRefPubMedPubMedCentral

143.

Taghavi N, Mohsenifar Z, Baghban AA, Arjomandkhah A. CD20+ tumor infiltrating B lymphocyte in oral squamous cell carcinoma: correlation with clinicopathologic characteristics and heat shock protein 70 expression. Pathol Res Int. 2018;2018:4810751. https://doi.org/10.1155/2018/4810751.CrossRef

144.

Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity. 2015;42(4):607–12. https://doi.org/10.1016/j.immuni.2015.04.005.CrossRefPubMed

145.

Distel LV, Fickenscher R, Dietel K, Hung A, Iro H, Zenk J, et al. Tumour infiltrating lymphocytes in squamous cell carcinoma of the oro- and hypopharynx: prognostic impact may depend on type of treatment and stage of disease. Oral Oncol. 2009;45(10):e167–74. https://doi.org/10.1016/j.oraloncology.2009.05.640.CrossRefPubMed

146.

Drayton DL, Liao S, Mounzer RH, Ruddle NH. Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol. 2006;7(4):344–53. https://doi.org/10.1038/ni1330.CrossRefPubMed

147.

Wirsing AM, Rikardsen OG, Steigen SE, Uhlin-Hansen L, Hadler-Olsen E. Characterisation and prognostic value of tertiary lymphoid structures in oral squamous cell carcinoma. BMC Clin Pathol. 2014;14:38. https://doi.org/10.1186/1472-6890-14-38.CrossRefPubMedPubMedCentral

148.

Shiga K, Hara M, Nagasaki T, Sato T, Takahashi H, Takeyama H. Cancer-associated fibroblasts: their characteristics and their roles in tumor growth. Cancers (Basel). 2015;7(4):2443–58. https://doi.org/10.3390/cancers7040902.CrossRef

149.

Harper J, Sainson RC. Regulation of the anti-tumour immune response by cancer-associated fibroblasts. Semin Cancer Biol. 2014;25:69–77. https://doi.org/10.1016/j.semcancer.2013.12.005.CrossRefPubMed

150.

Li H, Zhang J, Chen SW, Liu LL, Li L, Gao F, et al. Cancer-associated fibroblasts provide a suitable microenvironment for tumor development and progression in oral tongue squamous cancer. J Transl Med. 2015;13:198. https://doi.org/10.1186/s12967-015-0551-8.CrossRefPubMedPubMedCentral

151.

Lim KP, Cirillo N, Hassona Y, Wei W, Thurlow JK, Cheong SC, et al. Fibroblast gene expression profile reflects the stage of tumour progression in oral squamous cell carcinoma. J Pathol. 2011;223(4):459–69. https://doi.org/10.1002/path.2841.CrossRefPubMed

152.

Choi SY, Oh SY, Kang SH, Kang SM, Kim J, Lee HJ, et al. NAB 2-expressing cancer-associated fibroblast promotes hnscc progression. Cancers (Basel). 2019;11(3). https://doi.org/10.3390/cancers11030388.

153.

Yu B, Wu K, Wang X, Zhang J, Wang L, Jiang Y, et al. Periostin secreted by cancer-associated fibroblasts promotes cancer stemness in head and neck cancer by activating protein tyrosine kinase 7. Cell Death Dis. 2018;9(11):1082. https://doi.org/10.1038/s41419-018-1116-6.CrossRefPubMedPubMedCentral

154.

Dhanda J, Triantafyllou A, Liloglou T, Kalirai H, Lloyd B, Hanlon R, et al. SERPINE1 and SMA expression at the invasive front predict extracapsular spread and survival in oral squamous cell carcinoma. Br J Cancer. 2014;111(11):2114–21. https://doi.org/10.1038/bjc.2014.500.CrossRefPubMedPubMedCentral

155.

Lai SL, Tan ML, Hollows RJ, Robinson M, Ibrahim M, Margielewska S, et al. Collagen induces a more proliferative, migratory and chemoresistant phenotype in head and neck cancer via DDR1. Cancers (Basel). 2019;11(11). https://doi.org/10.3390/cancers11111766.

156.

• Puram SV, Tirosh I, Parikh AS, Patel AP, Yizhak K, Gillespie S, et al. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell. 2017;171(7):1611–24.e24. https://doi.org/10.1016/j.cell.2017.10.044Seminal paper using single cell transcriptomic analysis in HNSCC, finding a profound role for CAFs in promoting an EMT profile in tumor cells. CrossRefPubMedPubMedCentral

157.

Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82. https://doi.org/10.1038/nature14129.CrossRef

158.

Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24(5):541–50. https://doi.org/10.1038/s41591-018-0014-x.CrossRefPubMedPubMedCentral

159.

Lyu H, Li M, Jiang Z, Liu Z, Wang X. Correlate the TP53 mutation and the HRAS mutation with immune signatures in head and neck squamous cell cancer. Comput Struct Biotechnol J. 2019;17:1020–30. https://doi.org/10.1016/j.csbj.2019.07.009.CrossRefPubMedPubMedCentral

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The Immune Microenvironment in Head and Neck Squamous Cell Carcinoma: on Subsets and Subsites

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