Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Clinical Medicine Research Center, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Cancer Res. 2018 Oct 1;78(19):5586-5599. doi: 10.1158/0008-5472.CAN-17-3962. Epub 2018 Jul 16.
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 NFκB-transcribed COX-2, which catalyzed the synthesis of prostaglandin E (PGE). PGE exacerbated the immunosuppressive activity of MDSCs and accelerated tumor growth. Moreover, PGE suppressed RIPK3 expression while enhancing expression of NFκB and COX-2 in MDSCs and colorectal cancer cells. Inhibition of COX-2 or PGE 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 regulate tumor immunity, providing potential ideas for immunotherapy against colorectal cancer. A novel signaling circuit involving RIPK3 and PGE enhances accumulation and immunosuppressive activity of MDSCs, implicating its potential as a therapeutic target in anticancer immunotherapy. http://cancerres.aacrjournals.org/content/canres/78/19/5586/F1.large.jpg .
受体相互作用蛋白激酶 3（RIPK3）对于炎症性肠病（IBD）和结直肠癌中的黏膜修复至关重要。然而，其在肿瘤免疫中的作用尚不清楚。在这里，我们报告结直肠癌中 RIPK3 的减少与髓系来源的抑制细胞（MDSC）的积累有关。RIPK3 的缺乏通过 MDSC 的积累和免疫抑制活性促进了肿瘤发生。MDSC 和结直肠癌细胞中 RIPK3 的减少引发了 NFκB 转录的 COX-2，其催化前列腺素 E（PGE）的合成。PGE 加剧了 MDSC 的免疫抑制活性并加速了肿瘤生长。此外，PGE 抑制 MDSC 和结直肠癌细胞中 RIPK3 的表达，同时增强 NFκB 和 COX-2 的表达。COX-2 或 PGE 受体的抑制逆转了 MDSC 的免疫抑制活性并抑制了肿瘤发生。患者数据库还描绘了 RIPK3 和 COX-2 表达与结直肠癌生存的相关性。我们的研究结果表明了一个新的信号通路，即 RIPK3 和 PGE 调节肿瘤免疫，为结直肠癌的免疫治疗提供了潜在的思路。涉及 RIPK3 和 PGE 的新信号通路增强了 MDSC 的积累和免疫抑制活性，暗示其作为抗癌免疫治疗的潜在治疗靶点。
