Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression.
Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression.
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DOI：
10.1158/2159-8290.cd-15-1412
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发表时间：
2016-09
期刊：
影响因子：
28.2
通讯作者：
He YW
中科院分区：
文献类型：
--
作者：
Wang Y;Sun SN;Liu Q;Yu YY;Guo J;Wang K;Xing BC;Zheng QF;Campa MJ;Patz EF Jr;Li SY;He YW
与其对许多细胞的抑制作用相反，IL-10 可以激活 CD8+ 肿瘤浸润淋巴细胞 (TIL) 并增强其抗肿瘤活性。然而，CD8+ TIL 通常不表达 IL-10，因为自分泌补体 C3 通过补体受体 C3aR 和 C5aR 抑制 IL-10 的产生。然而，来自 C3 缺陷小鼠的 CD8+ TIL 表达 IL-10 并表现出增强的效应功能。 C3 缺陷小鼠以 T 细胞和 IL-10 依赖性方式抵抗肿瘤发展；与IL-2处理的TIL相比，用IL-2加IL-10扩增的人TIL在体外增加了对原发性肿瘤的杀伤力。补体介导的抗肿瘤免疫抑制独立于 PD-1/PD-L1 免疫检查点通路。我们的研究结果表明，CD8+ TIL 上表达的补体受体 C3aR 和 C5aR 代表了一类新型免疫检查点，可以作为肿瘤免疫治疗的目标。此外，在 TIL 扩增和用于过继细胞治疗的基因工程 T 细胞中掺入 IL-10 可增强其抗肿瘤功效。
In contrast to its inhibitory effects on many cells, IL-10 activates CD8+ tumor infiltrating lymphocytes (TILs) and enhances their antitumor activity. However, CD8+ TILs do not routinely express IL-10 as autocrine complement C3 inhibits IL-10 production through complement receptors C3aR and C5aR. CD8+ TILs from C3-deficient mice, however, express IL-10 and exhibit enhanced effector function. C3-deficient mice are resistant to tumor development in a T cell- and IL-10-dependent manner; human TILs expanded with IL-2 plus IL-10 increase the killing of primary tumors in vitro compared to IL-2 treated TILs. Complement-mediated inhibition of antitumor immunity is independent of the PD-1/PD-L1 immune checkpoint pathway. Our findings suggest that complement receptors C3aR and C5aR expressed on CD8+ TILs represent a novel class of immune checkpoints that could be targeted for tumor immunotherapy. Moreover, incorporation of IL-10 in the expansion of TILs and in gene-engineered T cells for adoptive cell therapy enhances their antitumor efficacy.