All -trans retinoic acid suppresses CD8+ T cell terminal exhaustion which enhances anti–PD-1 efficacy against glioblastoma [RNA-Seq]

Therefore, better understanding of the regulators of terminal exhaustion could overcome intrinsic resistance to ICB and thereby improve the efficacy of immunotherapy. In this study, we find that all-trans retinoic acid (ATRA) suppresses CD8⁺ T cell terminal exhaustion.

Administration of ATRA during CD8⁺ T cell activation in vitro conferred resistance to terminal exhaustion and preserved effector cytokine production and effector function. Mechanistically, ATRA selectively induced the expression of the long isoform of T cell factor 1 (TCF-1βBD), through activation of the canonical WNT/β-catenin pathway. In a mouse glioma model, adoptively transferred ATRA-conditioned CD8⁺ T cells exhibited exhaustion resistance, which led to superior tumor-infiltrating CD8+ T cell polyfunctionality and enhanced glioma suppression.