All-trans retinoic acid suppresses CD8+ T-cell terminal exhaustion and potentiates anti-PD-1 therapy in glioblastoma
Abstract
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, a better understanding of the regulators of terminal exhaustion could overcome intrinsic resistance to ICB and improve the efficacy of immunotherapy. In this study, we report that all-trans retinoic acid (ATRA) suppresses CD8⁺ T-cell terminal exhaustion. The 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 increased TCF-1βBD and β-catenin expression and resistance to exhaustion, which led to superior tumor-infiltrating CD8+ T-cell polyfunctionality and enhanced glioma suppression. Importantly, oral administration of ATRA also suppressed terminal exhaustion of tumor-infiltrating CD8+ T cells and synergized with anti-PD-1 therapy, overcoming resistance to immune checkpoint blockade (ICB) in two mouse models of glioma. Combined ATRA and anti-PD-1 treatment also displayed synergistic therapeutic potential by significantly reducing recurrence in a mouse model of glioma that had undergone surgical resection.…
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