The use of tumor mutation-derived neoantigen represents a promising approach for cancer vaccines. Preclinical and early-phase human clinical studies have shown the successful induction of tumor neoepitope-directed responses; however, overall clinical efficacy of neoantigen vaccines has been limited. One major obstacle of this strategy is the prevailing lack of sufficient understanding of the mechanism underlying the generation of neoantigen-specific CD8+ T cells. Here, we report a correlation between antitumor efficacy of neoantigen/toll-like receptor 3 (TLR3)/CD40 vaccination and the generation of antigen-specific CD8+ T cells expressing CX3C chemokine receptor 1 (CX3CR1) in a preclinical model. Mechanistic studies using mixed bone marrow chimeras identified that CD40 and CD80/86, but not CD70 signaling in Batf3-dependent conventional type 1 dendritic cells (cDC1s) is required for antitumor efficacy of neoantigen vaccine and generation of neoantigen-specific CX3CR1+ CD8+ T cells. Although CX3CR1+ CD8+ T cells exhibited robust in vitro effector function, depletion of this subset did not alter the antitumor efficacy of neoantigen/TLR3/CD40 agonists vaccination, suggesting that the expanded CX3CR1+ CD8+ T cell subset represents the post-differentiated in vivo effective CX3CR1-negative CD8+ T cell subset. Taken together, our results reveal a critical role of CD40 and CD80/86 signaling in cDC1s in antitumor efficacy of neoantigen-based therapeutic vaccines, and implicate the potential utility of CX3CR1 as a circulating predictive T-cell biomarker in vaccine therapy.

中文翻译：

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cDC1s中的CD40和CD80 / 86信号传导介导有效的新抗原疫苗接种和小鼠中抗原特异性CX3CR1 + CD8 + T细胞的产生

源自肿瘤突变的新抗原代表了用于癌症疫苗的有前途的方法。临床前和早期人类临床研究表明，成功诱导了肿瘤新表位定向反应。然而，新抗原疫苗的整体临床功效受到限制。该策略的一个主要障碍是对新抗原特异性CD8 + T细胞生成的潜在机制缺乏足够的了解。在这里，我们报告新抗原/通行费样受体3（TLR3）/ CD40疫苗的抗肿瘤功效与临床前模型中表达CX3C趋化因子受体1（CX3CR1）的抗原特异性CD8 + T细胞的产生之间的相关性。使用混合骨髓嵌合体进行的机理研究确定，CD40和CD80 / 86，但对于新抗原疫苗的抗肿瘤功效和新抗原特异性CX3CR1 + CD8 + T细胞的生成，不需要Batf3依赖的常规1型树突状细胞（cDC1s）中的CD70信号传导。尽管CX3CR1 + CD8 + T细胞表现出强大的体外效应器功能，但该亚型的消耗不会改变新抗原/ TLR3 / CD40激动剂疫苗的抗肿瘤效力，这表明扩展的CX3CR1 + CD8 + T细胞亚型代表了分化后的体内有效CX3CR1- CD8 + T细胞阴性。综上所述，我们的结果揭示了cDC1s中CD40和CD80 / 86信号在基于新抗原的治疗性疫苗的抗肿瘤功效中的关键作用，并暗示了CX3CR1作为循环性预测性T细胞生物标志物在疫苗治疗中的潜在效用。