A Critical Role of CD40 and CD70 Signaling in Conventional Type 1 Dendritic Cells in Expansion and Antitumor Efficacy of Adoptively Transferred Tumor-Specific T Cells

CD80 CD40 CD86 过继性细胞移植 生物 癌症研究 细胞生物学 免疫疗法 树突状细胞 CD8型 细胞毒性T细胞 肿瘤微环境 T细胞 免疫学 抗原 免疫系统 体外 生物化学
作者
Takaaki Oba,Toshifumi Hoki,Takayoshi Yamauchi,Tibor Keler,Henry C. Marsh,Xuefang Cao,Fumito Ito
出处
期刊:Journal of Immunology [The American Association of Immunologists]
卷期号:205 (7): 1867-1877 被引量:30
标识
DOI:10.4049/jimmunol.2000347
摘要

Abstract In vivo expansion of adoptively transferred CD8+ T cells is a critical determinant of successful adoptive T cell therapy. Emerging evidence indicates Batf3-dependent conventional type 1 dendritic cells (cDC1s) rarely found within the tumor myeloid compartment are crucial for effector T cell recruitment to the tumor microenvironment. However, the role of cDC1s in expansion of tumor-specific CD8+ T cells remains unclear. In this article, we addressed the role of cDC1s and their costimulatory molecules, CD40, CD70, and CD80/CD86, in expansion and antitumor efficacy of adoptively transferred in vitro–primed CD8+ T cells recognizing nonmutated tumor-associated self-antigens. We found that TLR/CD40–mediated expansion and antitumor efficacy of adoptively transferred tumor-specific CD8+ T cells were abrogated in Batf3−/− mice. Further mechanistic studies using mixed bone marrow chimeric mice identified that CD40 and CD70 but not CD80/CD86 signaling in cDC1s played a critical role in expansion and antitumor efficacy of adoptively transferred CD8+ T cells. Moreover, induction and activation of cDC1s by administration of FMS-like tyrosine kinase 3 ligand (Flt3L) and TLR/CD40 agonists augmented expansion of adoptively transferred CD8+ T cells, delayed tumor growth, and improved survival. These findings reveal a key role for CD40 and CD70 signaling in cDC1s and have major implications for the design of new vaccination strategies with adoptive T cell therapy.
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