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

Terminal exhaustion of CD8⁺ T cells limits the efficacy of immune checkpoint blockade (ICB), particularly in glioblastoma, which is characterized by an immunosuppressive tumor microenvironment. 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. Oral administration of ATRA also suppressed terminal exhaustion of tumor-infiltrating CD8+ T cells and synergized with anti-PD-1 therapy, overcoming resistance in mouse models of glioma. Synergistic ATRA administration and anti-PD-1 treatment displayed significant therapeutic potential in mouse recurrent glioma model. Single-cell transcriptomic analysis of glioblastoma patients receiving anti-PD-1 therapy revealed that CD8⁺ T cells from responders were enriched for retinoic acid responsive and WNT-associated gene signatures, which correlated with improved survival. These findings establish ATRA as a modulator of CD8⁺ T cell exhaustion by inducing WNT/β-catenin dependent TCF-1βBD expression. This pathway offers therapeutic potential to overcome resistance to ICB in glioma.