Targeting radiation induced CD4 CCR8 T cells enhances anti-tumor immunity and reduces recurrence in Head and Neck Squamous Cell Carcinoma 9382

Abstract Description Head and Neck Squamous Cell Carcinoma (HNSCC) is characterized by a high incidence of locoregional recurrence, which remains a leading cause of mortality. While immunotherapies targeting the PD-1/PD-L1 axis have improved overall survival in recurrent or metastatic settings, durable responses remain elusive, with many patients experiencing disease progression following immune checkpoint inhibitor (ICI) treatment. The mechanisms underlying recurrence in HNSCC remain poorly understood, necessitating innovative approaches to improve progression-free survival. In this study, we identify a novel immunosuppressive cell population in HNSCC, CD4+CCR8+ T cells. Using preclinical models, we show that CD4+CCR8+ cells represent a highly immunosuppressive, tumor-specific population induced by radiation therapy. Functionally, CCR8 marks a CD4 T cell population that suppresses anti-tumor immunity, presenting a previously uncharacterized mechanism of immune evasion. We demonstrate that radiation, combined with a CCR8-targeted depletion antibody, reprograms CD4 T cells towards a Th1 phenotype, enhances CD8 T cell cytotoxicity, and drives robust anti-tumor responses. In models of locoregional recurrence replicating clinical failure patterns, this combination therapy significantly prolongs progression-free survival. Mechanistically, CCR8 depletion promotes CD8 T cell memory formation within tumor-draining lymph nodes, suggesting durable immunological benefits against disease recurrence. Funding Sources Sana D. Karam is funded by the following grants: R01DE028529, R01CA28465, R01DE028282, 1P50CA261605-01, V Foundation, and the Wings of Hope Foundation for Pancreatic Cancer Research. She is also funded by a basic research grant provided by Amgen Pharmaceuticals. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)