Ripk3-induced inflammation by I-MDSCs promotes intestinal tumors

Myeloid derived suppressor cells (MDSC) promote colorectal cancer (CRC) 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 (ApcMin/+ 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 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 if Ripk3 regulates inflammatory cytokines in I-MDSCs to assess the non-immunosuppressive 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, ApcMin/+ mice and an MC38 transplantable tumor model. Mechanistically, Ripk3 signaling in I-MDSC increased tumor size by expanding IL-17 producing T cells in MC38 tumors. Collectively, these data suggest Ripk3 signaling as a potential therapeutic target in CRC.

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