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由凝集素途径促进的补体激活介导c3ar依赖性肉瘤的进展和免疫抑制

原文发布日期：2021-02-18

英文摘要：

摘要翻译：

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由凝集素途径促进的补体激活介导c3ar依赖性肉瘤的进展和免疫抑制

Complement activation promoted by the lectin pathway mediates C3aR-dependent sarcoma progression and immunosuppression

原文发布日期：2021-02-18

英文摘要：

Complement has emerged as a component of tumor-promoting inflammation. We conducted a systematic assessment of the role of complement activation and effector pathways in sarcomas. C3−/−, MBL1/2−/− and C4−/− mice showed reduced susceptibility to 3-methylcholanthrene sarcomagenesis and transplanted sarcomas, whereas C1q and factor B deficiency had marginal effects. Complement 3a receptor (C3aR), but not C5aR1 and C5aR2, deficiency mirrored the phenotype of C3−/− mice. C3 and C3aR deficiency were associated with reduced accumulation and functional skewing of tumor-associated macrophages, increased T-cell activation and response to anti-PD-1 therapy. Transcriptional profiling of sarcoma-infiltrating macrophages and monocytes revealed the enrichment of the major histocompatibility complex II–dependent antigen presentation pathway in C3-deficient cells. In patients, C3aR expression correlated with a macrophage population signature, and C3-deficiency-associated signatures predicted better clinical outcome. These results suggest that the lectin pathway and C3a–C3aR axis are key components of complement and macrophage-mediated sarcoma promotion and immunosuppression.

摘要翻译：

补体已 emerges 作为肿瘤促炎成分。为了系统评估激活及效应通路在软骨癌中的作用，我们进行了相关研究。C3−/−、MBL1/2−/− 和 C4−/− 小鼠相比，C1q 及因子 B 缺乏对 3-甲基-香草酸诱导的软骨癌易发性及移植癌发应答效果有限。补体 3a 接收器（C3aR），但不包括 C5aR1 和 C5aR2 缺乏，与 C3−/− 小鼠的表型相吻合。C3 及 C3aR 缺乏关联肿瘤相关巨噬细胞中肿瘤累积量减少及功能偏倚、T 细胞激活增强和对 PD-1 抗体治疗的应答增加。通过转录测序，发现软骨癌侵袭性巨噬细胞和单核细胞中显著富集了依赖 MHC II 表位的抗原呈递通路在 C3 缺乏细胞中。在患者中，C3aR 表达水平与一种巨噬细胞群标志特征相关联，而 C3 缺乏相关的表型标志特征可预测更好的临床预后。以上结果提示，由 lectin 通路及 C3a-C3aR 轴构成的补体及巨噬细胞在软骨癌发生和免疫抑制中发挥关键作用。