{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T01:12:57Z","timestamp":1783905177901,"version":"3.55.0"},"reference-count":31,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Dent Res"],"abstract":"<jats:p>\n                    Heterozygous mutations of the gene encoding caspase-8 protease occur in 10% of human head and neck squamous cell carcinomas (HNSCCs). Cell line studies indicate that these mutations block apoptosis induced by death ligands. However, the\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    role of caspase-8 mutations in the development of HNSCC and their impact on response to immune checkpoint blockade have not been determined. We generated mice with heterozygous, epithelium-specific knock-in of a representative, HNSCC-associated caspase-8 mutation (D305G). The impact of the\n                    <jats:italic toggle=\"yes\">caspase-8<\/jats:italic>\n                    mutation was assessed following treatment with the carcinogen 4-nitroquinoline-1-oxide (4NQO) in drinking water. Treatment of the D305G caspase-8 mutant mice with 4NQO resulted in a greater number of tongue tumors per mouse and a higher percentage of advanced-stage invasive carcinomas than was observed in 4NQO-treated mice with wild-type caspase-8, and tumors from the mutant mice were more resistant to anti\u2013PD-1. We also engineered the murine oral cancer cell line MOC1 for heterozygous expression of caspase-8 mutations. Tumors generated from these engineered cells in syngeneic, immunocompetent mice demonstrated reduced responsiveness to anti\u2013PD-1, relative to tumors with wild-type caspase-8. Further, the caspase-8 mutant tumors displayed reduced intratumoral and splenic CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells and impaired recruitment of monocytes and dendritic cells during PD-1 blockade. Collectively, these findings demonstrate that caspase-8 mutation promotes carcinogen-induced HNSCC development and resistance to anti\u2013PD-1. Investigation of caspase-8 mutations as potential biomarkers of poor response to immunotherapy in patients with HNSCC is warranted.\n                  <\/jats:p>","DOI":"10.1177\/00220345261457066","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T07:27:26Z","timestamp":1783582046000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Caspase-8 Mutation Promotes HNSCC Development and Resistance to Anti\u2013PD-1"],"prefix":"10.1177","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5983-0927","authenticated-orcid":false,"given":"Z.","family":"Cui","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, University of California\u2013San Francisco, San Francisco, CA, USA"},{"name":"Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New York, Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7687-1514","authenticated-orcid":false,"given":"H.","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New York, Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.C.","family":"Woerner","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, University of California\u2013San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.R.","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California\u2013San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.N.","family":"Peterson","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, University of California\u2013San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8552-8987","authenticated-orcid":false,"given":"N.K.","family":"VanLandingham","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, University of California\u2013San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Nazarenko","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, University of California\u2013San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.-O.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of California\u2013San Francisco, San Francisco, CA, USA"},{"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.R.","family":"Grandis","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, University of California\u2013San Francisco, San Francisco, CA, USA"},{"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.E.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, University of California\u2013San Francisco, San Francisco, CA, USA"},{"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"e_1_3_3_2_1","doi-asserted-by":"crossref","unstructured":"Agrawal N et al. 2011. 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PD-1 blockade on tumor microenvironment-resident ILC2s promotes TNF-\u03b1 production and restricts progression of metastatic melanoma. Front Immunol. 12:733136. https:\/\/doi.org\/10.3389\/fimmu.2021.733136","DOI":"10.3389\/fimmu.2021.733136"},{"key":"e_1_3_3_15_1","doi-asserted-by":"crossref","unstructured":"Johnson DE et al. 2020. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. 6(1):92. https:\/\/doi.org\/10.1038\/s41572-020-00224-3","DOI":"10.1038\/s41572-020-00224-3"},{"key":"e_1_3_3_16_1","doi-asserted-by":"crossref","unstructured":"Judd NP Allen CT Winkler AE Uppaluri R. 2012a. Comparative analysis of tumor-infiltrating lymphocytes in a syngeneic mouse model of oral cancer. Otolaryngol Head Neck Surg. 147(3):493\u2013500. https:\/\/doi.org\/10.1177\/0194599812442037","DOI":"10.1177\/0194599812442037"},{"key":"e_1_3_3_17_1","doi-asserted-by":"crossref","unstructured":"Judd NP et al. 2012b. ERK1\/2 regulation of CD44 modulates oral cancer aggressiveness. 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