The Interplay Between γδ T cells and B cells Contributes to Immune Checkpoint Inhibitor Resistance 3426

Abstract Description Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet resistance and immune-related adverse events (irAEs) remain significant challenges. γδ T cells and B cells are recognized as critical players in the tumor microenvironment (TME), but their roles in shaping T cell phenotypes and contributing to ICI resistance are not fully understood. Using syngeneic tumor models in autoimmune-prone NOD mice, which enable simultaneous profiling of tumor immunity and autoimmunity, we investigated mechanisms underlying ICI sensitivity and resistance. In the resistant tumor model, CD8+ T cells exhibit a naïve phenotype, with elevated TCF-1 expression and reduced activation markers such as PD-1 and CTLA-4. In contrast, activated CD8+ T cells dominate the sensitive tumor model, highlighting T cell phenotypes as key drivers of ICI responses. Further analyses implicated γδ T cells and B cells in these divergent responses. Depleting γδ T cells in the resistant model significantly improved tumor control, underscoring their role in mediating resistance. Conversely, CD8+ T cell activation was enhanced in B cell-deficient mice, suggesting B cells may restrict antitumor immunity. Together, these findings provide critical insights into the interplay between T cells, γδ T cells, and B cells within the TME and highlight potential therapeutic strategies to overcome ICI resistance without inducing irAEs. Funding Sources National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number: T32AI138945 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)