| First Author | Jayakumar A | Year | 2019 |
| Journal | Cancer Res | Volume | 79 |
| Issue | 7 | Pages | 1587-1599 |
| PubMed ID | 30786994 | Mgi Jnum | J:274184 |
| Mgi Id | MGI:6295008 | Doi | 10.1158/0008-5472.CAN-18-2153 |
| Citation | Jayakumar A, et al. (2019) RIPK3-Induced Inflammation by I-MDSCs Promotes Intestinal Tumors. Cancer Res 79(7):1587-1599 |
| abstractText | Myeloid-derived suppressor cells (MDSC) promote colorectal cancer by several mechanisms, including suppression of antitumor T cells and production of tumorigenic factors. We previously showed that an intermediate MDSC subset (I-MDSC) is expanded in an intestinal tumor model (Apc(Min/+) mice), but the importance of this subset in promoting tumors is unclear. Here, we show that I-MDSCs are a distinct heterogeneous subset due to differential and reduced expression of the monocytic marker, Ly6C, and granulocytic marker, Ly6G. Besides causing necroptotic cell death, receptor-interacting protein kinase 3 (RIPK3) has an alternate function as a signaling component inducing cytokine synthesis. We evaluated whether RIPK3 regulates inflammatory cytokines in I-MDSCs to assess the nonimmunosuppressive function of I-MDSCs in promoting tumors. Inhibition of RIPK3 with the commercially available small-molecule inhibitor GSK 872 showed that RIPK3-mediated inflammation promoted intestinal tumors in two intestinal tumor models, Apc(Min/+) mice and an MC38 transplantable tumor model. Mechanistically, RIPK3 signaling in I-MDSC increased tumor size by expanding IL17-producing T cells in MC38 tumors. Collectively, these data suggest RIPK3 signaling as a potential therapeutic target in colorectal cancer. SIGNIFICANCE: The specific role of RIPK3 in intestinal tumors and MDSC function sheds light on a key inflammatory mechanism driving tumorigenesis and allows for possible therapeutic intervention. |
