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Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>In view of improving biomarkers predicting the efficacy of immunotherapy for head and neck squamous cell carcinoma (R\/M HNSCC), this multicenter retrospective study aimed to identify clinical, tumor microenvironmental, and genomic factors that are related to therapeutic response to the anti- Programmed cell death protein 1 (PD-1) antibody, nivolumab, in patients with R\/M HNSCC. <\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-1 ligand (PD-L1) expression in immune cells as well as PD-L1 combined positive score (CPS) than non-responders. The frequency of natural killer cells was associated with nivolumab response in patients with prior cetuximab use, but not in cetuximab-na\u00efve status. Age-stratified analysis showed nivolumab response was linked to high CPS and lymphoid-inflamed profiles in patients aged \u2265 65. In contrast, lower NLR in peripheral blood counts was associated with response in patients aged &amp;lt; 65. Notably, <jats:italic>TP53<\/jats:italic> mutation-positive group had lower CPS and T cell densities, suggesting an immune-excluded microenvironment. Patients with altered tumor suppressor gene pathways, including <jats:italic>TP53<\/jats:italic>, <jats:italic>CDKN2A<\/jats:italic>, and <jats:italic>SMAD4<\/jats:italic> mutations, had lower CPS, higher smoking index, and were associated with poor responses. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Nivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1390873","type":"journal-article","created":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T04:38:09Z","timestamp":1722227889000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Clinical, genomic and immune microenvironmental determinants of nivolumab response in head and neck squamous cell 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