RIPK3-Induced Inflammation by I-MDSCs Promotes Intestinal Tumors

Cancer Res. 2019 Apr 1;79(7):1587-1599. doi: 10.1158/0008-5472.CAN-18-2153. Epub 2019 Feb 20.

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 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Colorectal Neoplasms / metabolism*
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Humans
  • Inflammation / metabolism*
  • Interleukins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myeloid-Derived Suppressor Cells / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*

Substances

  • Interleukins
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases