2. Academic Validation
  3. A RIPK3-PGE2 Circuit Mediates Myeloid-Derived Suppressor Cell-Potentiated Colorectal Carcinogenesis

A RIPK3-PGE2 Circuit Mediates Myeloid-Derived Suppressor Cell-Potentiated Colorectal Carcinogenesis

  • Cancer Res. 2018 Oct 1;78(19):5586-5599. doi: 10.1158/0008-5472.CAN-17-3962.
Guifang Yan  # 1 2,  Huakan Zhao  # 1 2,  Qi Zhang  # 1 2,  Yu Zhou 1 2,  Lei Wu 1 2,  Juan Lei 1 2,  Xiang Wang 1 2,  Jiangang Zhang 1 2,  Xiao Zhang 1 2,  Lu Zheng 3,  Guangsheng Du 4,  Weidong Xiao 4,  Bo Tang 5,  Hongming Miao 6,  Yongsheng Li 7 2
Affiliations

Affiliations

  • 1 Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
  • 2 Clinical Medicine Research Center, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
  • 3 Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
  • 4 Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
  • 5 Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
  • 6 Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing, China. hongmingmiao@sina.com yli@tmmu.edu.cn.
  • 7 Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China. hongmingmiao@sina.com yli@tmmu.edu.cn.
  • # Contributed equally.
PMID: 30012671 DOI: 10.1158/0008-5472.CAN-17-3962
Abstract

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 E2 (PGE2). PGE2 exacerbated the immunosuppressive activity of MDSCs and accelerated tumor growth. Moreover, PGE2 suppressed RIPK3 expression while enhancing expression of NFκB and COX-2 in MDSCs and colorectal Cancer cells. Inhibition of COX-2 or PGE2 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 PGE2 regulate tumor immunity, providing potential ideas for immunotherapy against colorectal Cancer.Significance: A novel signaling circuit involving RIPK3 and PGE2 enhances accumulation and immunosuppressive activity of MDSCs, implicating its potential as a therapeutic target in Anticancer immunotherapy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5586/F1.large.jpg Cancer Res; 78(19); 5586-99. ©2018 AACR.

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