Tumor-specific stem-like progenitor exhausted CD8+ T cell subsets diverge into terminally exhausted cells and long-lived memory T cells 3102

Abstract Description Chronic T cell stimulation in tumors and chronic viral infections leads to T cell exhaustion, a state of dysfunction. As the inhibitory receptor LAG3 is expressed by all exhausted T (TEX) cells, we generated a Lag3 lineage tracing mouse model (Lag3iCreERT2Rosa26LSL-tdTomato) to fate-map and characterize tumor-reactive LAG3+CD8+ TEX cells. In tumor-bearing mice, two distinct tdTomato+ CD8+ T cell subsets stratified by LAG3 surface expression (LAG3+tdT+ and LAG3-tdT+) exhibited contrasting anatomical distributions, functionality and transcriptional profiles, yet shared a common origin and TEX epigenetic state. While LAG3+tdT+CD8+ TEX cells were terminally exhausted and restricted to the tumor microenvironment, LAG3-tdT+CD8+ TEX cells were stem-like progenitors that persisted in vivo and formed the T cell memory pool. This study highlights TEX cell functional heterogeneity and plasticity, and characterizes a unique LAG3-tdT+ stem-like progenitor TEX subset that drives an anti-tumor memory response, supporting antibody-based therapeutic targeting of LAG3+ TEX cells to unleash anti-tumor immunity and promote durability. Funding Sources P01 AI108545 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)