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

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 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 .

Chemotaxis-driven delivery of nano-pathogenoids for complete eradication of tumors post-phototherapy

“…Moreover, blocking the interaction of CXCR2 with CXCL1 and MIP-2 using a small molecule CXCR2 inhibitor SB225002 significantly reduced the neutrophil recruitment (Supplementary Fig. 8) 5,[31][32][33] . Collectively, neutrophils migrated to PTT-treated tumors along chemokine gradients of CXCL1 and MIP-2, irrespective of the type of tumors and PTT transducers, as well as the tumor size.…”

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“…SART3 has been shown to induce both a humoral and cellular adaptive immune response in a vaccination study of patients with advanced colorectal cancer 67 . RIPK3 is a tumor suppressor whose downregulation has been associated with tumorigenesis, immunomodulation, and poor clinical prognosis in colorectal cancer 68,69 , although its exact role in the adaptive immunity is still under investigation. While confirmatory studies are needed, the present study in conjunction with supporting studies in other cancer types nominates potential immune biomarkers and therapeutic targets in mCRPC.…”

Metabolic Regulation of Myeloid-Derived Suppressor Cell Function in Cancer

“…A reduction of RIPK3 in colorectal cancer is related to the accumulation of MDSCs. Decreased RIPK3 activates nuclear factor kappa-B (NF-κB) to transcribe the cyclooxygenase-2 (COX2) gene to generate PGE2, an inhibitor of RIPK3, further suppressing RIPK3 [40]. Moreover, tumor necrosis factor (TNFα) also contributes to the survival of MDSCs by interacting with tumor necrosis factor receptor 2 (TNFR2) to upregulate cellular FLICE (FADD-like IL1β-converting enzyme)-inhibitory protein (c-FLIP) and reduce expression of the protease caspase 8 [30,41].…”

“…Impeding the immunosuppressive function of MDSCs is a major cancer treatment strategy. PGE2 induces MDSCs to express ARG1, which plays a major immunosuppressive role, while COX2 is an upstream signal of PGE2 [40]. Silencing COX2 significantly reduces MDSCs in the spleens of tumor-bearing mice [124].…”