{"id":41770,"date":"2025-08-29T18:51:09","date_gmt":"2025-08-29T16:51:09","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2025\/08\/29\/chronic-isg15-exposure-accelerates-cd8-t-cell-dysfunction-while-increasing-pd-1-blockade-sensitivity-in-oral-squamous-cell-carcinoma\/"},"modified":"2025-08-29T18:51:09","modified_gmt":"2025-08-29T16:51:09","slug":"chronic-isg15-exposure-accelerates-cd8-t-cell-dysfunction-while-increasing-pd-1-blockade-sensitivity-in-oral-squamous-cell-carcinoma","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2025\/08\/29\/chronic-isg15-exposure-accelerates-cd8-t-cell-dysfunction-while-increasing-pd-1-blockade-sensitivity-in-oral-squamous-cell-carcinoma\/","title":{"rendered":"Chronic ISG15 Exposure Accelerates CD8+ T-cell Dysfunction while Increasing PD-1 Blockade Sensitivity in Oral Squamous Cell Carcinoma"},"content":{"rendered":"<div>\n<p><b>Cancer Immunol Res<\/b>. 2025 Aug 29. doi: 10.1158\/2326-6066.CIR-25-0047. Online ahead of print.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>Immunotherapy has emerged as a promising treatment for head and neck squamous cell carcinoma (HNSCC), yet clinical responses remain limited. Elevated expression of interferon-stimulated gene 15 (ISG15), commonly observed in oral squamous cell carcinoma (OSCC), may contribute to this limited efficacy. Although chronic interferon signaling is known to impair CD8+ T cell function, the specific role of secreted ISG15 in T cell exhaustion remains unclear. Analysis of human OSCC datasets revealed significant enrichment of the ISG core score-including ISG15-in tumors compared to adjacent non-tumor tissues. Using a novel in vitro model of human T cell dysfunction, we found that acute ISG15 exposure enhances CD8+ T cell effector functions, whereas prolonged exposure induces severe dysfunction via a CD11a\/LFA-1-independent, endocytosis-dependent mechanism. In an immunocompetent orthotopic OSCC model, ISG15-expressing tumors exhibited accelerated growth and recruited more tumor-reactive CD8+ T cells; however, these cells were functionally impaired. Importantly, PD-1 blockade treatment significantly slowed tumor progression and restored T cell function in ISG15-expressing tumors. Together, our findings reveal that chronic ISG15 exposure promotes CD8+ T cell dysfunction, but these cells remain responsive to PD-1 blockade. This study identifies ISG15 as a potential biomarker for identifying patients likely to benefit from PD-1 blockade therapy.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/40879086\/?utm_source=SimplePie&amp;utm_medium=rss&amp;utm_content=101614637&amp;ff=20250829125106&amp;v=2.18.0.post9+e462414\">40879086<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1158\/2326-6066.CIR-25-0047\">10.1158\/2326-6066.CIR-25-0047<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>Cancer Immunol Res. 2025 Aug 29. doi: 10.1158\/2326-6066.CIR-25-0047. Online ahead of print. ABSTRACT Immunotherapy has emerged as a promising treatment for head and neck squamous cell carcinoma (HNSCC), yet clinical responses remain limited. Elevated expression of interferon-stimulated gene 15 (ISG15), commonly observed in oral squamous cell carcinoma (OSCC), may contribute to this limited efficacy. Although &#8230; <a title=\"Chronic ISG15 Exposure Accelerates CD8+ T-cell Dysfunction while Increasing PD-1 Blockade Sensitivity in Oral Squamous Cell Carcinoma\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2025\/08\/29\/chronic-isg15-exposure-accelerates-cd8-t-cell-dysfunction-while-increasing-pd-1-blockade-sensitivity-in-oral-squamous-cell-carcinoma\/\" aria-label=\"Read more about Chronic ISG15 Exposure Accelerates CD8+ T-cell Dysfunction while Increasing PD-1 Blockade Sensitivity in Oral Squamous Cell Carcinoma\">Read more<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[55,42],"tags":[],"class_list":["post-41770","post","type-post","status-publish","format-standard","hentry","category-cancer-immunology-reserch","category-publicaciones"],"_links":{"self":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/41770","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=41770"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/41770\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=41770"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=41770"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=41770"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}