CD47 blockade triggers T cell-mediated destruction of immunogenic tumors.
CD47 blockade triggers T cell-mediated destruction of immunogenic tumors.
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DOI：
10.1038/nm.3931
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发表时间：
2015-10
期刊：
影响因子：
82.9
通讯作者：
Xu MM
中科院分区：
文献类型：
--
作者：
Liu X;Pu Y;Cron K;Deng L;Kline J;Frazier WA;Xu H;Peng H;Fu YX;Xu MM
由CD47特异性阻断抗体介导的巨噬细胞吞噬肿瘤细胞已被认为是异种移植模型中的主要效应机制。使用同系免疫活性肿瘤模型，我们揭示了在CD47阻断的治疗效果依赖于树突状细胞（DC），而不是巨噬细胞交叉引发的T细胞免疫活性小鼠的反应。在T细胞缺陷型小鼠中，抗CD47抗体治疗的治疗效果被消除。此外，CD47阻断的抗肿瘤作用需要在CD11c+细胞中表达胞质DNA传感器STING，但既不表达MyD88也不表达TRIF，这表明来自肿瘤细胞的DNA的胞质传感通过抗CD47处理增强，进一步桥接先天性和适应性应答。值得注意的是，标准化疗的给药时机显著影响通过CD47阻断诱导抗肿瘤T细胞应答。总之，我们的研究结果表明，CD47阻断驱动T细胞介导的免疫原性肿瘤的消除。
Macrophage phagocytosis of tumor cells mediated by CD47-specific blocking antibodies has been proposed to be the major effector mechanism in xenograft models. Using syngeneic immunocompetent tumor models, we reveal that in the therapeutic effects of CD47 blockade depend on dendritic cell (DC) but not macrophage cross-priming of T cell responses in immunocompetent mice. The therapeutic effects of anti-CD47 antibody therapy were abrogated in T cell-deficient mice. In addition, the anti-tumor effects of CD47 blockade required expression of the cytosolic DNA sensor STING, but neither MyD88 nor TRIF, in CD11c+ cells, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 treatment, further bridging the innate and adaptive responses. Notably, the timing of administration of standard chemotherapy markedly impacted the induction of anti-tumor T cell responses by CD47 blockade. Together, our findings indicate that CD47 blockade drives T cell-mediated elimination of immunogenic tumors.