Tim-3-targeted vaccines overcome tumor immunosuppression and reduce cDC1 dependence to elicit potent anti-tumor immunity

• 成果类型: Article
• 署名作者: Fu, Chunmei; Ma, Tianle; Clausen, Bjorn E.; Mellman, Ira; Jiang, Aimin
• 署名单位: Henry Ford Health System; Henry Ford Hospital; Henry Ford Cancer Institute; Henry Ford Health System; Michigan State University; Michigan State University College of Human Medicine; Oakland University; Johannes Gutenberg University of Mainz; Johannes Gutenberg University of Mainz; University of California System; University of California San Francisco
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2518080123
• 发表日期: 2026-03-19
• 页码: e2518080123
• 关键词: dendritic cells; type 1 conventional DCs; type 2 conventional DCs; Tim-3-targeted vaccines; anti-tumor CD8 T cell immunity; MINOR H-ANTIGENS; dendritic cells; CANCER-IMMUNITY; CROSS-REACT; class-i; tim-3; responses; melanoma; DEC-205; immunization

摘要

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. Tese 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-(3-cateninactive mice, which model (3-catenin-driven DC dysfunction, Tim-3-targeted vaccination restored cross-priming and counteracted tumor-and DC-mediated immunosuppression. In Batf3-/- 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.