CD137 (4-1BB) Signaling Drives a TcR-Independent Exhaustion Program in CD8 T Cells

CD137 (4-1BB) activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by CD137 and its role in cancer immunosurveillance remain to be addressed. Here, we found that CD137 agonists rapidly induced CD8+ T cell chromatin remodeling and expression of exhausted T cell (Tex) specific genes. T cell-intrinsic, TCR independent, CD137 signaling involving the RelA and cRel NF-kB subunits stimulated the expansion of Tex cells characterized by the expression of multiple immune checkpoints (PD1, Tim3, Tigit) and reduced effector functions. Conversely, T cell-specific CD137 deletion limited the accumulation of Tex cells in different tumor mouse models. Yet, CD137-deficient CD8+ T cells failed to persist in tumors resulting in higher tumor burden in T cell-specific CD137-deficient mice. Understanding the cellular process that drive T cell dysfunction has crucial implications for the treatment of cancer and infectious diseases. Thus, this study, that uncovers the importance of CD137 signaling in T cell exhaustion program, could have broad applications for immunotherapy.Funding Information: This study has been partially supported through the grant EUR CARe N°ANR-18-EURE-0003 in the framework of the Programme des Investissements d'Avenir.Declaration of Interests: The authors declare no conflict of interest.Ethics Approval Statement: Animal experiments were conducted and approved by the Ministère de l'Enseignement Supérieur, de la Recherche et de l'Innovation (APAFIS#5614-20 16060815487810 v4) and are in compliance with the French regulations on care and protection of laboratory animals.