RIPK3-Induced Inflammation by I-MDSCs Promotes Intestinal Tumors

Cancer Research
Asha Jayakumar, Alfred L M Bothwell

Abstract

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 (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 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, ApcMin/+ 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 ...Continue Reading

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Citations

Oct 28, 2019·Journal of Cellular and Molecular Medicine·Yun-Jie ShiHao Wang
Aug 21, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Asha Jayakumar, Alfred L M Bothwell
May 16, 2019·Journal of Zhejiang University. Science. B·Fang ZhuSu-Dan He
Oct 15, 2020·Journal for Immunotherapy of Cancer·Yungang WangShengjun Wang
Dec 16, 2019·Ageing Research Reviews·Antero Salminen
May 12, 2021·Biochimica Et Biophysica Acta. Reviews on Cancer·Jingshan CaiShengjun Wang
Oct 17, 2021·Cellular and Molecular Life Sciences : CMLS·Shanhui LiuJiwang Zhang

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