Intracellular activation of complement C3 leads to PD-L1 antibody treatment resistance by modulating tumor-associated macrophages.
Intracellular activation of complement C3 leads to PD-L1 antibody treatment resistance by modulating tumor-associated macrophages.
复制标题
补体 C3 的细胞内激活通过调节肿瘤相关巨噬细胞导致 PD-L1 抗体治疗耐药。
DOI：
10.1158/2326-6066.cir-18-0272
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发表时间：
2019
影响因子：
10.1
通讯作者：
Zhu Bo
中科院分区：
文献类型：
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作者：
Zha Haoran;Wang Xinxin;Zhu Ying;Chen Dian-Gang;Han Xiao;Yang Fei;Gao Jianbao;Hu Chunyan;Shu Chi;Feng Yi;Tan Yulong;Zhang Jinyu;Li Yongsheng;Wan Yisong Y;Guo Bo;Zhu Bo
补体有助于构建免疫抑制肿瘤微环境。肿瘤细胞衍生的 C3 先前已被报道，但它是否以及如何作用于抗肿瘤免疫仍有待阐明。在这里，我们描述了肿瘤细胞来源的 C3 抑制抗肿瘤免疫的机制。肿瘤细胞衍生的 C3 在细胞内被激活，导致 C3a 的产生。 C3a 通过 C3a-C3aR-PI3Kγ 信号传导调节肿瘤相关巨噬细胞，从而抑制抗肿瘤免疫。在具有高 C3 表达的肿瘤细胞中删除 C3 可增强抗 PD-L1 治疗的功效。总的来说，我们的结果表明肿瘤细胞衍生的 C3 可能是癌症免疫治疗的有用靶点，并且靶向肿瘤细胞中的 C3 可能会增强抗肿瘤免疫力。
Complement aids in the construction of an immunosuppressive tumor microenvironment. Tumor cell–derived C3 has been previously reported, but whether and how it acts on antitumor immunity remains to be elucidated. Here, we describe a mechanism for tumor cell–derived C3 in suppressing antitumor immunity. Tumor cell–derived C3 was activated intracellularly, which results in generation of C3a. C3a modulated tumor-associated macrophages via C3a-C3aR-PI3Kγ signaling, thereby repressing antitumor immunity. Deletion of C3 in tumor cells that had high C3 expression enhanced efficacy of anti–PD-L1 treatment. Collectively, our results suggest tumor cell–derived C3 may be a useful target for cancer immunotherapy and that targeting C3 in tumor cells may enhance antitumor immunity.