Identifying key axis to modulate CD8 T cell exhaustion and improve cancer immunotherapy

Cancer Immunotherapy has revolutionized Clinical Oncology. Yet, CD8 T-cell exhaustion remains a leading cause of treatment failure. This hypofunctional program suppresses anti-tumor CD8 T-cell responses and is reinforced by a stable epigenetic program that prevents exhausted CD8 T-cells (Tex) from reverting to more functional states. Checkpoint inhibitors such as anti-PD-1 can temporally relieve some constraints on TEX and be curative. However, this approach alone does overcome the epigenetic restraints of exhaustion which likely explains the lack of long-term benefits in many patients. Combinatorial approaches are needed to achieve durable protection in more patients. Yet, an incomplete understanding of TEX biology has provided little rationale for relevant therapeutic interventions. Recent identification of an “effector-like” subset of TEX (TEX intermediate; TEXint) that mediates the benefits of PD-1 therapy and partially escapes the epigenetic strains of exhaustion, has brought new therapeutic perspective. Indeed, manipulating key pathways related to TEXint cells formation such as the IL-2/Stat5a axis potentiates TEX responses to PD-1 blockade and partially reprogram these cells towards more durably protective cell states. These findings provide compelling proof-of-concept that targeting key pathways driving Texint cell formation can unlock new strategies to overcome exhaustion and bolster PD-1 therapy. Building on this novel concept, our proposal utilizes advanced murine models alongside molecular engineering, large-scale genetic perturbation tools (CRISPR), and single-cell multiomics to uncover and characterize new regulatory pathways for Texint cell development. Our goal is to unveil new strategies to improve PD-1 therapy and advance next-generation anti-cancer immunotherapies.