Tumor microenvironment of head and neck squamous cell carcinomas
Authors:
Anna Fialová 1; Lucie Pavelková 2; Klára Plačková 1,2
Authors‘ workplace:
Sotio Biotech a. s., Praha, Česká republika
1; Klinika otorinolaryngologie a chirurgie hlavy a krku, 1. LF UK, FN v Motole, Praha, Česká republika
2
Published in:
Čes.-slov. Patol., 62, 2026, No. 2, p. 114-119
Category:
Reviews Article
Overview
The character of the tumor microenvironment is a relevant prognostic and predictive biomarker across a wide range of malignancies. The composition, density, and functional capacity of tumor-infiltrating immune cells are especially crucial for selecting suitable immunotherapy. Head and neck squamous cell carcinomas are considered immunologically hot tumors, with high numbers of tumor-infiltrating effector and regulatory T cells. Higher T cell counts, along with a better prognosis, were observed in patients with head and neck squamous cell carcinomas associated with human papillomavirus infection. The immune profile of smoking-associated tumors was more variable, with higher numbers of suppressive myeloid cells and a substantial variability in T cell numbers between the patients. Nevertheless, the high density of cytotoxic T cells was a stronger prognostic factor for head and neck squamous cell carcinoma patients than HPV status alone. Thus, prognostic markers based on knowledge of the tumor microenvironment and tumor-infiltrating immune cells could significantly improve patient stratification for immunotherapeutic and de-escalation treatment protocols.
Keywords:
HPV – head and neck squamous cell carcinoma – tumor microenvironment – HNSCC
Sources
1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024; 74(3): 229-263.
2. Gormley M, Creaney G, Schache A, Ingarfield K, Conway DI. Reviewing the epidemiology of head and neck cancer: Definitions, trends and risk factors. Br Dent J 2022; 233(9): 780-786.
3. Barsouk A, Aluru JS, Rawla P, Saginala K, Barsouk A. Epidemiology, risk factors, and prevention of head and neck squamous cell carcinoma. Med Sci (Basel) 2023; 11(2):
4. 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.
5. Lyssiotis CA, Kimmelman AC. Metabolic interactions in the tumor microenvironment. Trends Cell Biol 2017; 27(11): 863-875.
6. Wherry EJ. T cell exhaustion. Nat Immunol 2011; 12(6): 492-499.
7. Li X, Takahashi Y, Sakamoto K, Nakashima T. Expression of dendritic cell phenotypic antigens in cervical lymph nodes of patients with hypopharyngeal and laryngeal carcinoma. J Laryngol Otol Suppl 2009; 31): 5-10.
8. Li C, Shintani S, Terakado N, Nakashiro K, Hamakawa H. Infiltration of tumor-associated macrophages in human oral squamous cell carcinoma. Oncol Rep 2002; 9(6): 1219-1223.
9. Hartmann E, Wollenberg B, Rothenfusser S, et al. Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res 2003; 63(19): 6478-6487.
10. Bekeredjian-Ding I, Schafer M, Hartmann E, et al. Tumour-derived prostaglandin e and transforming growth factor-beta synergize to inhibit plasmacytoid dendritic cell-derived interferon-alpha. Immunology 2009; 128(3): 439-450.
11. Mlecnik B, Tosolini M, Kirilovsky A, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 2011; 29(6): 610-618.
12. Tang H, Qiao J, Fu YX. Immunotherapy and tumor microenvironment. Cancer Lett 2016; 370(1): 85-90.
13. Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci 2012; 125(Pt 23): 5591-5596.
14. Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov 2019; 18(3): 197-218.
15. Mandal R, Senbabaoglu Y, Desrichard A, et al. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight 2016; 1(17): e89829.
16. Cramer JD, Burtness B, Ferris RL. Immunotherapy for head and neck cancer: Recent advances and future directions. Oral Oncol 2019; 99(104460.
17. De Sousa LG, Ferrarotto R. Pembrolizumab in the first-line treatment of advanced head and neck cancer. Expert Rev Anticancer Ther 2021; 21(12): 1321-1331.
18. Burtness B, Harrington KJ, Greil R, 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(10212): 1915-1928.
19. Ferris RL, Blumenschein G, Jr., Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016; 375(19): 1856-1867.
20. Lydiatt WM, Patel SG, O’sullivan B, 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(2): 122-137.
21. Faraji F, Zaidi M, Fakhry C, Gaykalova DA. Molecular mechanisms of human papillomavirus-related carcinogenesis in head and neck cancer. Microbes Infect 2017; 19(9-10): 464 - 475.
22. Hladikova K, Koucky V, Boucek J, 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.
23. Nasman A, Romanitan M, Nordfors C, 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.
24. Solomon B, Young RJ, Bressel M, 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.
25. Gameiro SF, Ghasemi F, Barrett JW, 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.
26. Wansom D, Light E, Worden F, et al. Correlation of cellular immunity with human papillomavirus 16 status and outcome in patients with advanced oropharyngeal cancer. Arch Otolaryngol Head Neck Surg 2010; 136(12): 1267-1273.
27. Partlova S, Boucek J, Kloudova K, 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.
28. Badoual C, Hans S, Merillon 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): 128-138.
29. Elkoshi Z. On the prognostic power of tumor - -infiltrating lymphocytes - a critical commentary. Front Immunol 2022; 13(892543.
30. Semeraro M, Adam J, Stoll G, et al. The ratio of cd8(+)/foxp3 t lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ. Oncoimmunology 2016; 5(10): e1218106.
31. Dahlstrom KR, Anderson KS, Cheng JN, et al. Hpv serum antibodies as predictors of survival and disease progression in patients with hpv-positive squamous cell carcinoma of the oropharynx. Clin Cancer Res 2015; 21(12): 2861-2869.
32. Lechner A, Schlosser HA, Thelen M, et al. Tumor-associated b cells and humoral immune response in head and neck squamous cell carcinoma. Oncoimmunology 2019; 8(3): 1535293.
33. Kim SS, Shen S, Miyauchi S, et al. B cells improve overall survival in hpv-associated squamous cell carcinomas and are activated by radiation and pd-1 blockade. Clin Cancer Res 2020; 26(13): 3345-3359.
34. Ruffin AT, Cillo AR, Tabib T, et al. B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma. Nat Commun 2021; 12(1): 3349.
35. Zhu J, Lu H, Wang K, Liu B, Yan J. Tertiary lymphoid structures in head and neck squamous cell carcinoma. Transl Oncol 2024; 44(101949.
36. Syding LA, Plackova K, Pavelkova L, et al. High treg and pmn-mdsc densities are a hallmark of tertiary lymphoid structures in fatal cases of cervical cancer. J Immunother Cancer 2025; 13(9):
37. Imsirovic V, Wensveen FM, Polic B, Jelencic V. Maintaining the balance: Regulation of nk cell activity. Cells 2024; 13(17):
38. Messaoudene M, Frazao A, Gavlovsky PJ, et al. Patient’s natural killer cells in the era of targeted therapies: Role for tumor killers. Front Immunol 2017; 8(683.
39. Bisheshar SK, De Ruiter EJ, Devriese LA, Willems SM. The prognostic role of nk cells and their ligands in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis. Oncoimmunology 2020; 9(1): 1747345.
40. Stangl S, Tontcheva N, Sievert W, et al. Heat shock protein 70 and tumor-infiltrating nk cells as prognostic indicators for patients with squamous cell carcinoma of the head and neck after radiochemotherapy: A multicentre retrospective study of the german cancer consortium radiation oncology group (dktk - -rog). Int J Cancer 2018; 142(9): 1911-1925.
41. Goldman SA, Baker E, Weyant RJ, et al. Peritumoral cd1a-positive dendritic cells are associated with improved survival in patients with tongue carcinoma. Arch Otolaryngol Head Neck Surg 1998; 124(6): 641-646.
42. Kindt N, Descamps G, Seminerio I, 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.
43. Almansour S, Dunster JL, Crofts JJ, Nelson MR. Modelling the continuum of macrophage phenotypes and their role in inflammation. Math Biosci 2024; 377(109289.
44. Bisheshar SK, Van Der Kamp MF, De Ruiter EJ, et al. The prognostic role of tumor associated macrophages in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis. Oral Oncol 2022; 135(106227.
45. Kumar AT, Knops A, Swendseid B, et al. Prognostic significance of tumor-associated macrophage content in head and neck squamous cell carcinoma: A meta-analysis. Front Oncol 2019; 9(656.
46. Coffelt SB, Wellenstein MD, De Visser KE. Neutrophils in cancer: Neutral no more. Nat Rev Cancer 2016; 16(7): 431-446.
47. Rachidi S, Wallace K, Wrangle JM, et al. Neutrophil-to-lymphocyte ratio and overall survival in all sites of head and neck squamous cell carcinoma. Head Neck 2016; 38 Suppl 1(Suppl 1): E1068-1074.
48. Huang SH, Waldron JN, Milosevic M, et al. Prognostic value of pretreatment circulating neutrophils, monocytes, and lymphocytes in oropharyngeal cancer stratified by human papillomavirus status. Cancer 2015; 121(4): 545-555.
49. Varricchi G, Galdiero MR, Loffredo S, et al. Eosinophils: The unsung heroes in cancer? Oncoimmunology 2018; 7(2): e1393134.
50. Mascitti M, Togni L, Rubini C, et al. Tumour - -associated tissue eosinophilia (tate) in oral squamous cell carcinoma: A comprehensive review. Histol Histopathol 2021; 36(2): 113-122.
51. Dorta RG, Landman G, Kowalski LP, et al. Tumour-associated tissue eosinophilia as a prognostic factor in oral squamous cell carcinomas. Histopathology 2002; 41(2): 152-157.
52. De Paz D, Chang KP, Kao HK, et al. Clinical implications of tumor-associated tissue eosinophilia in tongue squamous cell carcinoma. Laryngoscope 2019; 129(5): 1123-1129.
53. Lee TL, Chen TH, Kuo YJ, et al. Tumor-associated tissue eosinophilia promotes angiogenesis and metastasis in head and neck squamous cell carcinoma. Neoplasia 2023; 35(100855.
54. Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol 2016; 37(3): 208-220.
55. Umansky V, Blattner C, Gebhardt C, Utikal J. The role of myeloid-derived suppressor cells (mdsc) in cancer progression. Vaccines (Basel) 2016; 4(4):
56. Lang S, Bruderek K, Kaspar C, et al. Clinical relevance and suppressive capacity of human myeloid-derived suppressor cell subsets. Clin Cancer Res 2018; 24(19): 4834-4844.
57. Greene S, Robbins Y, Mydlarz WK, 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(6): 1420-1431.
58. Vasquez-Dunddel D, Pan F, Zeng Q, et al. Stat3 regulates arginase-i in myeloid-derived suppressor cells from cancer patients. J Clin Invest 2013; 123(4): 1580-1589.
59. Knops AM, South A, Rodeck U, et al. Cancer-associated fibroblast density, prognostic characteristics, and recurrence in head and neck squamous cell carcinoma: A meta-analysis. Front Oncol 2020; 10(565306.
60. Markwell SM, Weed SA. Tumor and stromal - -based contributions to head and neck squamous cell carcinoma invasion. Cancers (Basel) 2015; 7(1): 382-406.
61. Pietras K, Ostman A. Hallmarks of cancer: Interactions with the tumor stroma. Exp Cell Res 2010; 316(8): 1324-1331.
62. Hu C, Zhang Y, Wu C, Huang Q. Heterogeneity of cancer-associated fibroblasts in head and neck squamous cell carcinoma: Opportunities and challenges. Cell Death Discov 2023; 9(1): 124.
Labels
Anatomical pathology Forensic medical examiner ToxicologyArticle was published in
Czecho-Slovak Pathology
2026 Issue 2
Most read in this issue
- News in the 5th edition of the WHO Classification of Tumours of the Head and Neck: Tumours of the Sinonasal Tract and Skull Base Tumors
- The most important news in head and neck pathology published since the release of the 5th edition of the WHO Classification of Head and Neck Tumors
- Lymphocytic Myocarditis – A New Histopathological Definition and Classification for Endomyocardial Biopsies, Surgical and Autopsy Specimens (“Seaport Criteria”)
- Časopis v nové podobě