Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Improving head and neck cancer therapies by immunomodulation of the tumour microenvironment

Nature Reviews Cancer volume 23, pages 173–188 (2023)Cite this article

Subjects

Abstract

Targeted immunotherapy has improved patient survival in head and neck squamous cell carcinoma (HNSCC), but less than 20% of patients produce a durable response to these treatments. Thus, new immunotherapies that consider all key players of the complex HNSCC tumour microenvironment (TME) are necessary to further enhance tumour-specific T cell responses in patients. HNSCC is an ideal tumour type in which to evaluate immune and non-immune cell differences because of two distinct TME aetiologies (human papillomavirus (HPV)-positive and HPV-negative disease), multiple anatomic sites for tumour growth, and clear distinctions between patients with locally advanced disease and those with recurrent and/or metastatic disease. Recent technological and scientific advancements have provided a more complete picture of all cellular constituents within this complex TME and have evaluated the interplay of both immune and non-immune cells within HNSCC. Here, we include a comprehensive analysis of the complete ecosystem of the HNSCC TME, performed utilizing data-rich resources such as The Cancer Genome Atlas, and cutting-edge techniques, such as single-cell RNA sequencing, high-dimensional flow cytometry and spatial multispectral imaging, to generate improved treatment strategies for this diverse disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Novel technologies have begun to elucidate the clear complexity of the HNSCC TME.
Fig. 2: New T cell targets in the HNSCC TME.
Fig. 3: Increasing cellular interactions with tertiary lymphoid structures in the HNSCC TME for maximal humoral and cellular immunity.
Fig. 4: Innate cell interactions generate inflammatory signals that drive outcomes in patients with HNSCC.
Fig. 5: The stromal microenvironment is functionally important for the HNSCC TME.
Fig. 6: Immune and non-immune therapeutic targets in the HNSCC TME.

Similar content being viewed by others

References

  1. Ferlay, J. et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int. J. Cancer 144, 1941–1953 (2019).

    Article  CAS  PubMed  Google Scholar 

  2. Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021).

    Article  PubMed  Google Scholar 

  3. Johnson, D. E. et al. Head and neck squamous cell carcinoma. Nat. Rev. Dis. Prim. 6, 92 (2020).

    Article  PubMed  Google Scholar 

  4. HHS.gov. Smoking Cessation: A Report of the Surgeon General — Key Findings https://www.hhs.gov/surgeongeneral/reports-and-publications/tobacco/2020-cessation-sgr-factsheet-key-findings/index.html#:~:Text=2020%20Surgeon%20General’s%20Report%20Findings,a%20decade%20to%20life%20expectancy (2020).

  5. Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).

    Article  PubMed  Google Scholar 

  6. Chaturvedi, A. K. et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J. Clin. Oncol. 29, 4294–4301 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Powell, S. F., Vu, L., Spanos, W. C. & Pyeon, D. The key differences between human papillomavirus-positive and -negative head and neck cancers: biological and clinical implications. Cancers 13, 5206 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ferris, R. L. et al. Nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: efficacy and safety in CheckMate 141 by prior cetuximab use. Clin. Cancer Res. 25, 5221–5230 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bonner, J. A. et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 354, 567–578 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Cramer, J. D., Burtness, B. & Ferris, R. L. Immunotherapy for head and neck cancer: recent advances and future directions. Oral. Oncol. 99, 104460 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li, L. et al. Comprehensive immunogenomic landscape analysis of prognosis-related genes in head and neck cancer. Sci. Rep. 10, 6395 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mito, I. et al. Comprehensive analysis of immune cell enrichment in the tumor microenvironment of head and neck squamous cell carcinoma. Sci. Rep. 11, 16134 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mandal, R. et al. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight 1, e89829 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Jiang, A.-M. et al. Tumor mutation burden, immune cell infiltration, and construction of immune-related genes prognostic model in head and neck cancer. Int. J. Med. Sci. 18, 226–238 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chen, X. et al. Immunological network analysis in HPV associated head and neck squamous cancer and implications for disease prognosis. Mol. Immunol. 96, 28–36 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–560 (2020).

    Article  CAS  PubMed  Google Scholar 

  17. Ruffin, A. T. et al. B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma. Nat. Commun. 12, 3349 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wood, O. 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 7, 56781–56797 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wuerdemann, N. et al. LAG-3, TIM-3 and VISTA expression on tumor-infiltrating lymphocytes in oropharyngeal squamous cell carcinoma-potential biomarkers for targeted therapy concepts. Int. J. Mol. Sci. 22, 379 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lechner, A. et al. Characterization of tumor-associated T-lymphocyte subsets and immune checkpoint molecules in head and neck squamous cell carcinoma. Oncotarget 8, 44418–44433 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Liu, Z. et al. Novel effector phenotype of Tim-3+ regulatory T cells leads to enhanced suppressive function in head and neck cancer patients. Clin. Cancer Res. 24, 4529–4538 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu, J.-F. et al. Blockade of TIM3 relieves immunosuppression through reducing regulatory T cells in head and neck cancer. J. Exp. Clin. Cancer Res. 37, 44 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Duhen, T. et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat. Commun. 9, 2724 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hwang, B., Lee, J. H. & Bang, D. Single-cell RNA sequencing technologies and bioinformatics pipelines. Exp. Mol. Med. 50, 1–14 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kuksin, M. et al. Applications of single-cell and bulk RNA sequencing in onco-immunology. Eur. J. Cancer 149, 193–210 (2021).

    Article  CAS  PubMed  Google Scholar 

  26. Chaudhry, F. et al. Single-cell RNA sequencing of the cardiovascular system: new looks for old diseases. Front. Cardiovasc. Med. 6, 173 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li, X. & Wang, C.-Y. From bulk, single-cell to spatial RNA sequencing. Int. J. Oral. Sci. 13, 36 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kürten, C. H. L. et al. Investigating immune and non-immune cell interactions in head and neck tumors by single-cell RNA sequencing. Nat. Commun. 12, 7338 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Cillo, A. R. et al. Immune landscape of viral- and carcinogen-driven head and neck cancer. Immunity 52, 183–199.e9 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Puram, S. V. et al. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell 171, 1611–1624.e24 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhang, Q. et al. Integrated analysis of single-cell RNA-seq and bulk RNA-seq reveals distinct cancer-associated fibroblasts in head and neck squamous cell carcinoma. Ann. Transl. Med. 9, 1017 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nordfors, C. 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 49, 2522–2530 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Wuerdemann, N. et al. PD-L1 expression and a high tumor infiltrate of CD8+ lymphocytes predict outcome in patients with oropharyngeal squamous cells carcinoma. Int. J. Mol. Sci. 21, 5228 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhou, Z. et al. PD-L1 in combination with CD8+ TIL and HIF-1α are promising prognosis predictors of head and neck squamous cell carcinoma. Cancer Manag. Res. 12, 13233–13239 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xiao, Y. et al. CD103+ T and dendritic cells indicate a favorable prognosis in oral cancer. J. Dent. Res. 98, 1480–1487 (2019).

    Article  CAS  PubMed  Google Scholar 

  36. McKinney, E. F. & Smith, K. G. T cell exhaustion and immune-mediated disease-the potential for therapeutic exhaustion. Curr. Opin. Immunol. 43, 74–80 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wherry, E. J. T cell exhaustion. Nat. Immunol. 12, 492–499 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Beltra, J.-C. et al. Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity 52, 825–841.e8 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kansy, B. A. et al. PD-1 status in CD8+ T cells associates with survival and anti-PD-1 therapeutic outcomes in head and neck cancer. Cancer Res. 77, 6353–6364 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Eberhardt, C. S. et al. Functional HPV-specific PD-1+ stem-like CD8 T cells in head and neck cancer. Nature 597, 279–284 (2021).

    Article  CAS  PubMed  Google Scholar 

  42. Wang, D. et al. A comprehensive profile of TCF1+ progenitor and TCF1- terminally exhausted PD-1+CD8+ T cells in head and neck squamous cell carcinoma: implications for prognosis and immunotherapy. Int. J. Oral. Sci. 14, 8 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Borst, J., Ahrends, T., Bąbała, N., Melief, C. J. M. & Kastenmüller, W. CD4+ T cell help in cancer immunology and immunotherapy. Nat. Rev. Immunol. 18, 635–647 (2018).

    Article  CAS  PubMed  Google Scholar 

  44. Tay, R. E., Richardson, E. K. & Toh, H. C. Revisiting the role of CD4+ T cells in cancer immunotherapy-new insights into old paradigms. Cancer Gene Ther. 28, 5–17 (2021).

    Article  CAS  PubMed  Google Scholar 

  45. Tesmer, L. A., Lundy, S. K., Sarkar, S. & Fox, D. A. Th17 cells in human disease. Immunol. Rev. 223, 87–113 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ye, J., Livergood, R. S. & Peng, G. The role and regulation of human Th17 cells in tumor immunity. Am. J. Pathol. 182, 10–20 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gameiro, S. F. et al. Treatment-naïve HPV+ head and neck cancers display a T-cell-inflamed phenotype distinct from their HPV- counterparts that has implications for immunotherapy. Oncoimmunology 7, e1498439 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Bhatt, K. H. et al. Profiling HPV-16-specific T cell responses reveals broad antigen reactivities in oropharyngeal cancer patients. J. Exp. Med. 217, e20200389 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Albers, A. et al. Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck. Cancer Res. 65, 11146–11155 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Welters, M. J. P. 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. 24, 634–647 (2018).

    Article  CAS  PubMed  Google Scholar 

  51. Kesselring, R., Thiel, A., Pries, R., Trenkle, T. & Wollenberg, B. Human Th17 cells can be induced through head and neck cancer and have a functional impact on HNSCC development. Br. J. Cancer 103, 1245–1254 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Li, C., Zhao, Y., Zhang, W. & Zhang, W. Increased prevalence of T(H)17 cells in the peripheral blood of patients with head and neck squamous cell carcinoma. Oral. Surg. Oral. Med. Oral. Pathol. Oral. Radiol. Endod. 112, 81–89 (2011).

    Article  PubMed  Google Scholar 

  53. Yang, M. et al. CXCL13 shapes immunoactive tumor microenvironment and enhances the efficacy of PD-1 checkpoint blockade in high-grade serous ovarian cancer. J. Immunother. Cancer 9, e001136 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Niogret, J. et al. Follicular helper-T cells restore CD8+-dependent antitumor immunity and anti-PD-L1/PD-1 efficacy. J. Immunother. Cancer 9, e002157 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Kim, S. T. et al. Human extrafollicular CD4+ Th cells help memory B cells produce Igs. J. Immunol. 201, 1359–1372 (2018).

    Article  CAS  PubMed  Google Scholar 

  56. Tahiliani, V., Hutchinson, T. E., Abboud, G., Croft, M. & Salek-Ardakani, S. OX40 Cooperates with ICOS to amplify follicular Th cell development and germinal center reactions during infection. J. Immunol. 198, 218–228 (2017).

    Article  CAS  PubMed  Google Scholar 

  57. Zotos, D. et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J. Exp. Med. 207, 365–378 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dadey, R. E., Workman, C. J. & Vignali, D. A. A. Regulatory T cells in the tumor microenvironment. Adv. Exp. Med. Biol. 1273, 105–134 (2020).

    Article  CAS  PubMed  Google Scholar 

  59. Sawant, D. V. et al. Adaptive plasticity of IL-10+ and IL-35+ Treg cells cooperatively promotes tumor T cell exhaustion. Nat. Immunol. 20, 724–735 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Jie, H. B. et al. Intratumoral regulatory T cells upregulate immunosuppressive molecules in head and neck cancer patients. Br. J. Cancer 109, 2629–2635 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chuckran, C. A. et al. Prevalence of intratumoral regulatory T cells expressing neuropilin-1 is associated with poorer outcomes in patients with cancer. Sci. Transl. Med. 13, eabf8495 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Strauss, L., Bergmann, C., Gooding, W., Johnson, J. T. & Whiteside, T. L. The frequency and suppressor function of CD4+CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck. Clin. Cancer Res. 13, 6301–6311 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Jie, H.-B. et al. CTLA-4+ regulatory T cells increased in cetuximab-treated head and neck cancer patients suppress NK cell cytotoxicity and correlate with poor prognosis. Cancer Res. 75, 2200–2210 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Oida, T., Xu, L., Weiner, H. L., Kitani, A. & Strober, W. TGF-beta-mediated suppression by CD4+CD25+ T cells is facilitated by CTLA-4 signaling. J. Immunol. 177, 2331–2339 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Chuckran, C. A., Liu, C., Bruno, T. C., Workman, C. J. & Vignali, D. A. Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy. J. Immunother. Cancer 8, e000967 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Economopoulou, P., Kotsantis, I. & Psyrri, A. The promise of immunotherapy in head and neck squamous cell carcinoma: combinatorial immunotherapy approaches. ESMO Open 1, e000122 (2016).

    Article  PubMed  Google Scholar 

  67. Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257–1265 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Janjic, B. M., Kulkarni, A., Ferris, R. L., Vujanovic, L. & Vujanovic, N. L. Human B cells mediate innate anti-cancer cytotoxicity through concurrent engagement of multiple TNF superfamily ligands. Front. Immunol. 13, 837842 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nelson, B. H. CD20+ B cells: the other tumor-infiltrating lymphocytes. J. Immunol. 185, 4977–4982 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Sharonov, G. V., Serebrovskaya, E. O., Yuzhakova, D. V., Britanova, O. V. & Chudakov, D. M. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat. Rev. Immunol. 20, 294–307 (2020).

    Article  CAS  PubMed  Google Scholar 

  71. Yuen, G. J., Demissie, E. & Pillai, S. B lymphocytes and cancer: a love-hate relationship. Trends Cancer 2, 747–757 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Shen, P. & Fillatreau, S. Antibody-independent functions of B cells: a focus on cytokines. Nat. Rev. Immunol. 15, 441–451 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Germain, C., Gnjatic, S. & Dieu-Nosjean, M.-C. Tertiary lymphoid structure-associated B cells are key players in anti-tumor immunity. Front. Immunol. 6, 67 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Bruno, T. C. et al. Antigen-presenting intratumoral B cells affect CD4+ TIL phenotypes in non-small cell lung cancer patients. Cancer Immunol. Res. 5, 898–907 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sautès-Fridman, C. et al. Tertiary lymphoid structures and B cells: clinical impact and therapeutic modulation in cancer. Semin. Immunol. 48, 101406 (2020).

    Article  PubMed  Google Scholar 

  76. Kim, S. 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. 26, 3345–3359 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lechner, A. et al. Tumor-associated B cells and humoral immune response in head and neck squamous cell carcinoma. Oncoimmunology 8, 1535293 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Russell, S. et al. Immune cell infiltration patterns and survival in head and neck squamous cell carcinoma. Head. Neck Oncol. 5, 24 (2013).

    PubMed  Google Scholar 

  80. Li, Q. et al. Prognostic value of tertiary lymphoid structure and tumour infiltrating lymphocytes in oral squamous cell carcinoma. Int. J. Oral. Sci. 12, 24 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Pretscher, D. et al. 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 9, 292 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Wieland, A. et al. Defining HPV-specific B cell responses in patients with head and neck cancer. Nature 597, 274–278 (2021).

    Article  CAS  PubMed  Google Scholar 

  83. Jeske, S. S. et al. Adenosine-producing regulatory B cells in head and neck cancer. Cancer Immunol. Immunother. 69, 1205–1216 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hladíková, K. 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 7, 261 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  85. van Erp, E. A., Luytjes, W., Ferwerda, G. & van Kasteren, P. B. Fc-Mediated antibody effector functions during respiratory syncytial virus infection and disease. Front. Immunol. 10, 548 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Gül, N. & van Egmond, M. Antibody-dependent phagocytosis of tumor cells by macrophages: a potent effector mechanism of monoclonal antibody therapy of cancer. Cancer Res. 75, 5008–5013 (2015).

    Article  PubMed  Google Scholar 

  87. Bald, T., Krummel, M. F., Smyth, M. J. & Barry, K. C. The NK cell-cancer cycle: advances and new challenges in NK cell-based immunotherapies. Nat. Immunol. 21, 835–847 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Concha-Benavente, F. et al. PD-L1 mediates dysfunction in activated PD-1+ NK cells in head and neck cancer patients. Cancer Immunol. Res. 6, 1548–1560 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Vujanovic, L., Ballard, W., Thorne, S. H., Vujanovic, N. L. & Butterfield, L. H. Adenovirus-engineered human dendritic cells induce natural killer cell chemotaxis via CXCL8/IL-8 and CXCL10/IP-10. Oncoimmunology 1, 448–457 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Vujanovic, L. et al. CD56dim CD16- natural killer cell profiling in melanoma patients receiving a cancer vaccine and interferon-α. Front. Immunol. 10, 14 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Stabile, H. et al. Reconstitution of multifunctional CD56lowCD16low natural killer cell subset in children with acute leukemia given α/β T cell-depleted HLA-haploidentical haematopoietic stem cell transplantation. Oncoimmunology 6, e1342024 (2017).

    Article  PubMed  Google Scholar 

  92. Wagner, S. et al. CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma. Int. J. Cancer 138, 2263–2273 (2016).

    Article  CAS  PubMed  Google Scholar 

  93. Lisco, A. et al. Treatment of relapsing HPV diseases by restored function of natural killer cells. N. Engl. J. Med. 385, 921–929 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Srivastava, R. M. et al. Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients. Clin. Cancer Res. 19, 1858–1872 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kurai, J. et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin. Cancer Res. 13, 1552–1561 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. López-Albaitero, A. et al. Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells. Cancer Immunol. Immunother. 58, 1853–1864 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Ma, Y., Shurin, G. V., Peiyuan, Z. & Shurin, M. R. Dendritic cells in the cancer microenvironment. J. Cancer 4, 36–44 (2013).

    Article  CAS  PubMed  Google Scholar 

  98. Gerosa, F. et al. Reciprocal activating interaction between natural killer cells and dendritic cells. J. Exp. Med. 195, 327–333 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Jardim, J. F., Gondak, R., Galvis, M. M., Pinto, C. A. L. & Kowalski, L. P. A decreased peritumoral CD1a+ cell number predicts a worse prognosis in oral squamous cell carcinoma. Histopathology 72, 905–913 (2018).

    Article  PubMed  Google Scholar 

  100. Reichert, T. E., Scheuer, C., Day, R., Wagner, W. & Whiteside, T. L. The number of intratumoral dendritic cells and zeta-chain expression in T cells as prognostic and survival biomarkers in patients with oral carcinoma. Cancer 91, 2136–2147 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Partlová, S. 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 4, e965570 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Kindt, N. et al. Langerhans cell number is a strong and independent prognostic factor for head and neck squamous cell carcinomas. Oral. Oncol. 62, 1–10 (2016).

    Article  PubMed  Google Scholar 

  103. Guess, J. C. & McCance, D. J. 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. 79, 14852–14862 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Vujanovic, L. et al. Virally infected and matured human dendritic cells activate natural killer cells via cooperative activity of plasma membrane-bound TNF and IL-15. Blood 116, 575–583 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Wculek, S. K. et al. Dendritic cells in cancer immunology and immunotherapy. Nat. Rev. Immunol. 20, 7–24 (2020).

    Article  CAS  PubMed  Google Scholar 

  106. Utispan, K. & Koontongkaew, S. Fibroblasts and macrophages: key players in the head and neck cancer microenvironment. J. Oral. Biosci. 59, 23–30 (2017).

    Article  Google Scholar 

  107. Hu, Y. 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. 35, 12 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Marcus, B. et al. Prognostic factors in oral cavity and oropharyngeal squamous cell carcinoma. Cancer 101, 2779–2787 (2004).

    Article  PubMed  Google Scholar 

  110. Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kwak, T. et al. Distinct populations of immune-suppressive macrophages differentiate from monocytic myeloid-derived suppressor cells in cancer. Cell Rep. 33, 108571 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Cai, H., Zhang, Y., Wang, J. & Gu, J. Defects in macrophage reprogramming in cancer therapy: the negative impact of PD-L1/PD-1. Front. Immunol. 12, 690869 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Sinha, P., Clements, V. K., Bunt, S. K., Albelda, S. M. & Ostrand-Rosenberg, S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J. Immunol. 179, 977–983 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Fu, E. et al. M2 macrophages reduce the radiosensitivity of head and neck cancer by releasing HB-EGF. Oncol. Rep. 44, 698–710 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Krneta, T. et al. M2-polarized and tumor-associated macrophages alter NK cell phenotype and function in a contact-dependent manner. J. Leukoc. Biol. 101, 285–295 (2017).

    Article  CAS  PubMed  Google Scholar 

  117. Pan, Y., Yu, Y., Wang, X. & Zhang, T. Tumor-associated macrophages in tumor immunity. Front. Immunol. 11, 583084 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ugel, S., De Sanctis, F., Mandruzzato, S. & Bronte, V. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J. Clin. Invest. 125, 3365–3376 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Balermpas, P. 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 111, 1509–1518 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Veglia, F., Sanseviero, E. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat. Rev. Immunol. 21, 485–498 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Gong, L. et al. Comprehensive single-cell sequencing reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of nasopharyngeal carcinoma. Nat. Commun. 12, 1540 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Ma, X. et al. LncRNAs as an intermediate in HPV16 promoting myeloid-derived suppressor cell recruitment of head and neck squamous cell carcinoma. Oncotarget 8, 42061–42075 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Meyer, C. et al. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol. Immunother. 63, 247–257 (2014).

    Article  CAS  PubMed  Google Scholar 

  125. Mao, L. et al. TIGIT/CD155 blockade enhances anti-PD-L1 therapy in head and neck squamous cell carcinoma by targeting myeloid-derived suppressor cells. Oral. Oncol. 121, 105472 (2021).

    Article  CAS  PubMed  Google Scholar 

  126. Highfill, S. L. et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci. Transl. Med. 6, 237ra67 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Kumar, V. et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 32, 654–668.e5 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kalinski, P. Regulation of immune responses by prostaglandin E2. J. Immunol. 188, 21–28 (2012).

    Article  CAS  PubMed  Google Scholar 

  129. Marvel, D. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J. Clin. Invest. 125, 3356–3364 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Davis, R. J. et al. Anti-PD-L1 efficacy can be enhanced by inhibition of myeloid-derived suppressor cells with a selective inhibitor of PI3Kδ/γ. Cancer Res. 77, 2607–2619 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Sobo-Vujanovic, A. et al. Inhibition of soluble tumor necrosis factor prevents chemically induced carcinogenesis in mice. Cancer Immunol. Res. 4, 441–451 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Knops, A. M. et al. Cancer-associated fibroblast density, prognostic characteristics, and recurrence in head and neck squamous cell carcinoma: a meta-analysis. Front. Oncol. 10, 565306 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Zhou, B. et al. A role for cancer-associated fibroblasts in inducing the epithelial-to-mesenchymal transition in human tongue squamous cell carcinoma. J. Oral. Pathol. Med. 43, 585–592 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Costea, D. E. et al. Identification of two distinct carcinoma-associated fibroblast subtypes with differential tumor-promoting abilities in oral squamous cell carcinoma. Cancer Res. 73, 3888–3901 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Bienkowska, K. J., Hanley, C. J. & Thomas, G. J. Cancer-associated fibroblasts in oral cancer: a current perspective on function and potential for therapeutic targeting. Front. Oral. Health 2, 686337 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Valkenburg, K. C., de Groot, A. E. & Pienta, K. J. Targeting the tumour stroma to improve cancer therapy. Nat. Rev. Clin. Oncol. 15, 366–381 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Kumar, D. et al. Cancer-associated fibroblasts drive glycolysis in a targetable signaling loop implicated in head and neck squamous cell carcinoma progression. Cancer Res. 78, 3769–3782 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Kang, S. H. et al. Cancer-associated fibroblast subgroups showing differential promoting effect on HNSCC progression. Cancers 13, 654 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Wheeler, S. E. et al. Enhancement of head and neck squamous cell carcinoma proliferation, invasion, and metastasis by tumor-associated fibroblasts in preclinical models. Head. Neck 36, 385–392 (2014).

    Article  PubMed  Google Scholar 

  140. Wu, X. et al. Mesenchymal stromal cell therapies: immunomodulatory properties and clinical progress. Stem Cell Res. Ther. 11, 345 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Kansy, B. A. et al. The bidirectional tumor–mesenchymal stromal cell interaction promotes the progression of head and neck cancer. Stem Cell Res. Ther. 5, 95 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Liu, C. et al. Bone marrow mesenchymal stem cells interact with head and neck squamous cell carcinoma cells to promote cancer progression and drug resistance. Neoplasia 23, 118–128 (2021).

    Article  CAS  PubMed  Google Scholar 

  143. Liotta, F. et al. Mesenchymal stem cells are enriched in head neck squamous cell carcinoma, correlates with tumour size and inhibit T-cell proliferation. Br. J. Cancer 112, 745–754 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Mazzoni, A. et al. Human T cells interacting with HNSCC-derived mesenchymal stromal cells acquire tissue-resident memory like properties. Eur. J. Immunol. 50, 1571–1579 (2020).

    Article  CAS  PubMed  Google Scholar 

  145. Ang, K. K. et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N. Engl. J. Med. 363, 24–35 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. O’Sullivan, B. et al. Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study. Lancet Oncol. 17, 440–451 (2016).

    Article  PubMed  Google Scholar 

  147. Lee, N. Y. et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 22, 450–462 (2021).

    Article  CAS  PubMed  Google Scholar 

  148. Fakhry, C. et al. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. J. Clin. Oncol. 32, 3365–3373 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Ferris, R. L. et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 375, 1856–1867 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Sacco, A. G. et al. Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial. Lancet Oncol. 22, 883–892 (2021).

    Article  CAS  PubMed  Google Scholar 

  151. Burtness, B. 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 394, 1915–1928 (2019).

    Article  CAS  PubMed  Google Scholar 

  152. Argiris, A. et al. LBA36 Nivolumab (N) + ipilimumab (I) vs EXTREME as first-line (1L) treatment (tx) for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): final results of CheckMate 651. Ann. Oncol. https://doi.org/10.1016/j.annonc.2021.08.2113 (2021).

    Article  Google Scholar 

  153. Astrazeneca. Update on KESTREL Phase III trial of Imfinzi with or without Tremelimumab in the 1st-line Treatment of Recurrent or Metastatic Head and Neck Cancer https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/update-on-kestrel-phase-iii-trial-for-imfinzi.html (2021).

  154. GSK. GSK Provides Update on Feladilimab, An Investigational Inducible T Cell Co-stimulatory (ICOS) Agonist https://www.gsk.com/en-gb/media/press-releases/gsk-provides-update-on-feladilimab-an-investigational-inducible-t-cell-co-stimulatory-icos-agonist/ (2021).

  155. Cohen, R. B. et al. Combination of monalizumab and cetuximab in recurrent or metastatic head and neck cancer patients previously treated with platinum-based chemotherapy and PD-(L)1 inhibitors. J. Clin. Oncol. 38, 6516–6516 (2020).

    Article  Google Scholar 

  156. Massarelli, E. 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. 5, 67–73 (2019).

    Article  PubMed  Google Scholar 

  157. Doran, S. L. et al. T-cell receptor gene therapy for human papillomavirus-associated epithelial cancers: a first-in-human, phase I/II Study. J. Clin. Oncol. 37, 2759–2768 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Nagarsheth, N. B. et al. TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat. Med. 27, 419–425 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Seiwert, T. Y. et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 17, 956–965 (2016).

    Article  CAS  PubMed  Google Scholar 

  160. Ferris, R. L. et al. Abstract CT021: Tumor-associated immune cell PD-L1 expression and peripheral immune profiling: Analyses from CheckMate 141. In Clinical Trials CT021-CT021 (American Association for Cancer Research, 2017).

  161. Chow, L. Q. M. et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J. Clin. Oncol. 34, 3838–3845 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Zandberg, D. P. et al. Tumor hypoxia is associated with resistance to PD-1 blockade in squamous cell carcinoma of the head and neck. J. Immunother. Cancer 9, e002088 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Ferris, R. L. et al. Nivolumab vs investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral. Oncol. 81, 45–51 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Watermann, C. et al. Recurrent HNSCC harbor an immunosuppressive tumor immune microenvironment suggesting successful tumor immune evasion. Clin. Cancer Res. 27, 632–644 (2021).

    Article  CAS  PubMed  Google Scholar 

  165. Lu, N. et al. Human Semaphorin-4A drives Th2 responses by binding to receptor ILT-4. Nat. Commun. 9, 742 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Böttcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037.e14 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Park, M. H., Lee, J. S. & Yoon, J. H. High expression of CX3CL1 by tumor cells correlates with a good prognosis and increased tumor-infiltrating CD8+ T cells, natural killer cells, and dendritic cells in breast carcinoma. J. Surg. Oncol. 106, 386–392 (2012).

    Article  CAS  PubMed  Google Scholar 

  168. Schumacher, T. N. & Thommen, D. S. Tertiary lymphoid structures in cancer. Science https://doi.org/10.1126/science.abf9419 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

    Ayana T. Ruffin, Housaiyin Li, Lazar Vujanovic, Dan P. Zandberg, Robert L. Ferris & Tullia C. Bruno

  2. Tumour Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Ayana T. Ruffin, Housaiyin Li, Lazar Vujanovic, Dan P. Zandberg, Robert L. Ferris & Tullia C. Bruno

  3. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA

    Ayana T. Ruffin, Robert L. Ferris & Tullia C. Bruno

  4. Graduate Program of Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Ayana T. Ruffin

  5. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA

    Housaiyin Li, Lazar Vujanovic & Robert L. Ferris

  6. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Housaiyin Li

  7. Molecular Genetics and Developmental Biology (MGDB) Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Housaiyin Li

Authors
  1. Ayana T. Ruffin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Housaiyin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lazar Vujanovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dan P. Zandberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert L. Ferris
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tullia C. Bruno
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article and wrote the article. R.L.F, T.B. and D.Z. contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Robert L. Ferris or Tullia C. Bruno.

Ethics declarations

Competing interests

L.V. is a co-inventor of a methodology licensed to INmune Bio, Inc., where soluble TNF sequestration using DN-TNF can be used to prevent or treat malignancies. D.P.Z. declares competing interests with Blueprint Medicines (advisory board), Macrogenics (consulting), Prelude Therapeutics (advisory board), and Merck (advisory board) and research support (institutional) from Merck, BMS, AstraZeneca, GlaxoSmithKline, Aduro, Astellas, Macrogenics, Lilly, Bicara, Checkmate Pharma, and Novasenta. R.L.F. declares competing interests with Aduro Biotech, Inc. (consulting), AstraZeneca/MedImmune (clinical trial, research funding), Bristol-Myers Squibb (advisory board, clinical trial, research funding), EMD Serono (advisory board), MacroGenics Inc. (advisory board), Merck (advisory board, clinical trial), Novasenta (consulting, stock, research funding), Numab Therapeutics AG (advisory board), Pfizer (advisory board), Sanofi (consultant), Tesaro (research funding) and Zymeworks Inc. (consultant). T.C.B. declares competing interests with Walking Fish Therapeutics (Scientific Advisory Board). The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Cancer thanks Zhijun Sun, Rieneke van de Ven and Moshe Elkabets for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ruffin, A.T., Li, H., Vujanovic, L. et al. Improving head and neck cancer therapies by immunomodulation of the tumour microenvironment. Nat Rev Cancer 23, 173–188 (2023). https://doi.org/10.1038/s41568-022-00531-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-022-00531-9

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing