A RIPK3-PGE2 Circuit Mediates Myeloid-Derived Suppressor Cell-Potentiated Colorectal Carcinogenesis
A RIPK3-PGE2 Circuit Mediates Myeloid-Derived Suppressor Cell-Potentiated Colorectal Carcinogenesis
复制标题
RIPK3-PGE(2) 电路介导骨髓源性抑制细胞增强的结直肠癌发生。
DOI：
10.1158/0008-5472.can-17-3962
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发表时间：
2018-10-01
期刊：
影响因子：
11.2
通讯作者：
Li, Yongsheng
中科院分区：
文献类型：
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作者：
Yan, Guifang;Zhao, Huakan;Li, Yongsheng
受体相互作用蛋白激酶3(RIPK3)在炎症性肠病(IBD)和结直肠癌的粘膜修复中起重要作用。然而，它在肿瘤免疫中的作用尚不清楚。在这里，我们报告了结直肠癌中RIPK3的降低与髓系来源的抑制细胞(MDSC)的积聚有关。RIPK3缺乏通过MDSCs的聚集和免疫抑制活性促进肿瘤的发生。MDSC和结直肠癌细胞中RIPK3的减少可诱导NFkB转录的COX-2，进而催化前列腺素E-2(PGE(2))的合成。PGE(2)加重MDSCs的免疫抑制活性，加速肿瘤生长。此外，PGE2抑制MDSCs和结直肠癌细胞中RIPK3的表达，而促进核因子kappaB和COX-2的表达。抑制COX-2或PGE(2)受体逆转了MDSCs的免疫抑制活性，抑制了肿瘤的发生。患者数据库还描述了RIPK3和COX-2的表达与结直肠癌生存率的相关性。我们的发现显示了一个新的信号通路，RIPK3和PGE(2)通过它调节肿瘤免疫，为抗结直肠癌的免疫治疗提供了潜在的思路。意义：一个新的信号通路涉及RIPK3和PGE(2)增强MDSCs的聚集和免疫抑制活性，暗示其作为抗癌免疫治疗的治疗靶点的潜力。(C)2018年AACR。
Receptor-interacting protein kinase 3 (RIPK3) is essential for mucosal repair in inflammatory bowel diseases (IBD) and colorectal cancer. However, its role in tumor immunity is unknown. Here, we report that decreased RIPK3 in colorectal cancer correlates with the accumulation of myeloid-derived suppressor cells (MDSC). Deficiency of RIPK3 boosted tumorigenesis via accumulation and immunosuppressive activity of MDSCs. Reduction of RIPK3 in MDSC and colorectal cancer cells elicited NFkB-transcribed COX-2, which catalyzed the synthesis of prostaglandin E-2 (PGE(2)). PGE(2) exacerbated the immunosuppressive activity of MDSCs and accelerated tumor growth. Moreover, PGE2 suppressed RIPK3 expression while enhancing expression of NF kappa B and COX-2 in MDSCs and colorectal cancer cells. Inhibition of COX-2 or PGE(2) receptors reversed the immunosuppressive activity of MDSCs and dampened tumorigenesis. Patient databases also delineated the correlation of RIPK3 and COX-2 expression with colorectal cancer survival. Our findings demonstrate a novel signaling circuit by which RIPK3 and PGE(2) regulate tumor immunity, providing potential ideas for immunotherapy against colorectal cancer.Significance: A novel signaling circuit involving RIPK3 and PGE(2) enhances accumulation and immunosuppressive activity of MDSCs, implicating its potential as a therapeutic target in anticancer immunotherapy. (C) 2018 AACR.