C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation
C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation
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DOI：
10.7150/thno.45058
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Hu, Weiguo
中科院分区：
文献类型：
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作者：
Ding, Peipei;Li, Ling;Hu, Weiguo
许多因素被认为在结直肠癌（CRC）的肿瘤发生中起重要作用，包括骨髓源性抑制细胞（MDSCs）和其他免疫细胞、细胞因子和趋化因子；然而，结直肠肿瘤发生的确切机制仍然难以捉摸，并且缺乏有效的预防治疗。在这里，我们研究了补体系统在结直肠肿瘤发生中的作用，补体系统是免疫监测和体内平衡的关键调节因子。方法：以野生型（WT）、C3-、C5-、C5ar1-和c5ar2缺陷小鼠为研究对象，联合给药偶氮氧甲烷(AOM)/葡聚糖硫酸钠（DSS）建立CRC模型。采用流式细胞术、免疫组化染色和多头实验对免疫细胞、细胞因子和趋化因子进行了分析。采用骨髓移植来确定免疫细胞在结直肠肿瘤发生中的作用。此外，我们使用C5aR1拮抗剂PMX205来研究其在结直肠肿瘤发生中的保护作用。结果：补体在AOM/ dss诱导的小鼠CRC模型炎症组织中被广泛激活，导致多方面的后果。补体C5，尤其是C5ar1的缺乏，而不是C3的缺乏几乎完全阻止了CRC的发生。C5a/C5aR1信号将MDSCs招募到发炎的结直肠，损害CD8(+) T细胞，并调节关键细胞因子和趋化因子的产生，从而引发结直肠癌。此外，C5aR1拮抗剂PMX205强烈阻碍结直肠癌的发生。骨髓移植进一步揭示免疫细胞表达C5aR1在结直肠肿瘤发生中起关键作用。结论：我们的研究确定了C5a/C5aR1信号在结直肠癌肿瘤发生中是一个重要的免疫调节程序，并提出了可行的预防策略。
Numerous factors have been claimed to play important roles in colorectal cancer (CRC) tumorigenesis, including myeloid-derived suppressor cells (MDSCs) and other immune cells, cytokines, and chemokines; however, the precise mechanisms of colorectal tumorigenesis remain elusive, and there is a lack of effective preventive treatments. Here, we investigated the role of complement system, a key regulator of immune surveillance and homeostasis, in colorectal tumorigenesis.Methods: The prototypical CRC model was induced by combined administration of azoxymethane (AOM)/dextran sulfate sodium (DSS) in Wild-type (WT), C3-, C5-, C5ar1-, and C5ar2-deficient mice. Using flow cytometry, immunohistochemical staining and multiplex bead assay, we profiled the immune cells, cytokines and chemokines. Bone marrow transplantation was employed to determine the contribution of immune cells in colorectal tumorigenesis. Further, we used C5aR1 antagonist PMX205 to investigate the protective role in colorectal tumorigenesis.Results: Complement was extensively activated in inflamed tissues of AOM/DSS-induced murine CRC model, leading to multifaceted consequences. The deficiency of complement C5 or especially C5ar1, but not C3 almost completely prevented CRC tumorigenesis. C5a/C5aR1 signaling recruited MDSCs into the inflamed colorectum to impair CD8(+) T cells, and modulated the production of critical cytokines and chemokines, thus initiating CRC. Moreover, the C5aR1 antagonist PMX205 strongly impeded colorectal tumorigenesis. Bone marrow transplantation further revealed that C5aR1 expression by immune cells was critical for colorectal tumorigenesis.Conclusion: Our study identifies C5a/C5aR1 signaling as a vital immunomodulatory program in CRC tumorigenesis and suggests a feasible preventive strategy.