Abstract B009: Caspase-8 mutation promotes head and neck squamous cell carcinoma development and resistance to anti-PD-1

Abstract Purpose: Heterozygous mutations in the gene encoding the caspase-8 protease are present in approximately 10% of head and neck squamous cell carcinoma (HNSCC) tumors, where studies indicate they block apoptosis induced by death ligands. However, the role of caspase-8 mutations in HNSCC development in vivo and their influence on response to programmed cell death-1 (PD-1) targeting agents remain unclear. Experimental Design: To investigate the role of caspase-8 mutation in HNSCC, we generated mice with an epithelium-specific, heterozygous knock-in of a representative HNSCC-associated caspase-8 mutation (D305G), regulated by the endogenous caspase-8 promoter. The impact of this mutation was assessed following carcinogen (4-nitroquinoline-1-oxide, 4NQO) treatment in drinking water. Additionally, to evaluate the effects of heterozygous caspase-8 mutations on anti-PD-1 responsiveness, murine HNSCC tumors were established in immunocompetent mice using MOC1 cells engineered to express mutant caspase-8.Results: Mice harboring the D305G caspase-8 mutation developed a higher number of tongue tumors per mouse and showed a greater incidence of advanced invasive carcinomas following 4NQO treatment compared to wild-type caspase-8 controls. In MOC1 tumor models, knockout or heterozygous expression of HNSCC-associated caspase-8 mutants significantly reduced sensitivity to anti-PD-1 therapy, in contrast to tumors derived from parental MOC1 cells. Conclusions: These findings reveal that caspase-8 mutations enhance carcinogen-induced HNSCC progression and confer resistance to anti-PD-1 therapy. Further investigation into caspase-8 mutations as biomarkers for poor immunotherapy response in HNSCC patients is warranted. Citation Format: Zhibin Cui, Liam C Woerner, Steven R Long, Christopher N Peterson, Nathan K VanLandingham, Andrew Nazarenko, Jennifer R Grandis, Daniel E Johnson. Caspase-8 mutation promotes head and neck squamous cell carcinoma development and resistance to anti-PD-1 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B009.