Tim-3-targeted vaccines overcome tumor immunosuppression and reduce cDC1 dependence to elicit potent anti-tumor immunity
Menée à l'aide de modèles murins de tumeurs, cette étude met en évidence l'intérêt des vaccins ciblant le récepteur transmembranaire TIM3 pour lever l'immunosuppression tumorale et induire une immunité antitumorale puissante sans dépendre des cellules dendritiques de type 1
Conventional type 1 dendritic cells (cDC1s) are specialized for cross-presenting tumor antigens and determining the efficacy of immunotherapies, including immune checkpoint blockade and adoptive cell therapy. However, their rarity and tumor-induced dysfunction severely limit CD8 T cell priming and represent a central bottleneck to therapeutic efficacy. While strategies such as anti–DEC-205-mediated antigen delivery and Flt3L-driven DC expansion can enhance host DC function, their reliance on functional cDC1s remains a significant constraint. We developed Tim-3-targeted vaccines by conjugating tumor antigens or neoantigens to anti–Tim-3 antibodies. These vaccines delivered antigens to both cDC1s and cDC2s, and elicited robust, durable CD8 T cell responses. Remarkably, Tim-3-targeted vaccines endowed cDC2s with efficient cross-presentation capacity that matched that of cDC1s. In tumor-bearing mice or in CD11c-
β-cateninactive mice, which model β-catenin-driven DC dysfunction, Tim-3-targeted vaccination restored cross-priming and counteracted tumor- and DC-mediated immunosuppression. In Batf3
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mice lacking cDC1s, anti-Tim-3-based vaccines still elicited significant CD8 T cell cross-priming and tumor control—albeit both were reduced compared to wild-type mice— demonstrating that cDC1s contribute to but are not essential for Tim-3-targeted vaccine–induced CD8 T cell priming and anti-tumor efficacy. Strikingly, a single dose of anti-Tim-3–neoantigen vaccination eradicated large established MC38 tumors in a CD8 T cell–dependent manner. Together, these data identify Tim-3-targeted vaccines as a next-generation cancer vaccine platform that broadens DC engagement, reduces reliance on cDC1s, and overcomes tumor- and DC-mediated immunosuppression, addressing key limitations of current DC-based cancer vaccines.
Proceedings of the National Academy of Sciences , article en libre accès, 2026