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

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.

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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.

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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.

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

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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.

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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

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