Ionizing radiation impairs the efficacy of immune checkpoint inhibition by driving terminal exhaustion of progenitor exhausted CD8+ T cells 4054

Abstract Description Persistent antigen exposure, a hallmark of chronic infections and tumors, drives the formation of a distinct population of CD8+ T cells, known as exhausted CD8+ T (TEX) cells, with increased expression of immune checkpoint molecules and reduced effector function. Immune checkpoint inhibition (ICI) therapy has emerged as a powerful tool to reinvigorate the function of TEX cells. However, despite the immunostimulatory effects of radiotherapy (RT), combining RT with ICI has yielded modest clinical benefits in cancer patients. While the success of ICI therapy largely depends on the presence of progenitor TEX cells, the impact of high-dose ionizing radiation (IR) on the TEX population, particularly enriched within the treatment field, remains understudied. Here, we show that chronically infected mice with LCMV-Clone 13 subjected to sublethal whole-body irradiation (WBI) exhibited a lasting numerical decline and impaired antigen-specific function in their TEX cells. Using single-cell RNA sequencing and multiparameter flow cytometry, we observed that WBI gradually altered the subset composition of surviving TEX cells, highlighted by the loss of progenitor and effector-like TEX cells while terminally-exhausted TEX cells were enriched. Lastly, WBI rendered ICI therapy less effective in rescuing TEX cells and decreasing viral burden. These findings provide important insights into how high-dose IR alters the fate of TEX cells, potentially impairing their responsiveness to ICI therapy. Funding Sources Supported by NIH Grants GM134880, AI114543 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)