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

ABSTRACT: Terminal exhaustion of CD8⁺ T cells limits the efficacy of immune checkpoint blockade, particularly in glioblastoma, which is characterized by an immunosuppressive tumor microenvironment. Therefore, better understanding of the regulators of terminal exhaustion could improve the efficacy of immunotherapy and overcome intrinsic resistance. In this study, we find that all-trans retinoic acid (ATRA) suppresses CD8⁺ T cell terminal exhaustion. Administration of ATRA during CD8⁺ T cell priming by chronic exposure to glioma cells 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-1p45), through activation of the canonical WNT/β-catenin pathway. Silencing β-catenin abrogated TCF-1p45 expression and reversed the exhaustion-resistant phenotype of CD8+ T cells. Moreover, in a mouse glioma model, ATRA administration promoted CD8⁺ T cell exhaustion resistance, which led to superior tumor-infiltrating CD8+ T cell polyfunctionality and enhanced anti-glioma responses. Oral administration of ATRA also synergized with anti–PD-1 therapy, overcoming resistance in two mouse models of glioma. Single-cell transcriptomic analysis of anti–PD-1–treated glioblastoma patients 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 suppressor of CD8⁺ T cell exhaustion by inducing WNT/β-catenin–dependent TCF-1p45 expression. This pathway offers therapeutic potential to overcome resistance to immune checkpoint blockade in glioma, and it may also offer strategies to improve cell therapies, such as adoptive cell transfer.

ORGANISM(S): Mus musculus

PROVIDER: GSE296984 | GEO | 2026/09/09

REPOSITORIES: GEO