RIPK3-Induced Inflammation by I-MDSCs Promotes Intestinal Tumors

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 (Apc Min/þ 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 nonimmunosuppres-sive 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/þ 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.

Specific Commensal Bacterium Critically Regulates Gut Microbiota Osteoimmunomodulatory Actions During Normal Postpubertal Skeletal Growth and Maturation

“…MDSCs derive from the bone marrow where they make‐up roughly 30% of the normal marrow composition . MDSCs produce proinflammatory cytokines that can induce naïve CD4 + cells into T H 17/IL17A + cells . Moreover, MDSCs are profoundly increased in proinflammatory states and have been shown to act as osteoclast precursors under pathologic conditions .…”

“…(59,99) MDSCs produce proinflammatory cytokines that can induce naïve CD4 + cells into T H 17/IL17A + cells. (100) Moreover, MDSCs are profoundly increased in proinflammatory states and have been shown to act as osteoclast precursors under pathologic conditions. (101)(102)(103) SFB presence in the complex commensal gut microbiota promoted MDSC expansion in bone marrow, which may have contributed to the increased marrow T H 17 cells and enhanced osteoclastic phenotype found in MPF versus EF mice.…”

Toll‐like receptor 4 regulates spontaneous intestinal tumorigenesis by up‐regulating IL‐6 and GM‐CSF

“…Ripk3 signalling promotes intestinal tumours by up-regulating cytokines IL23 and IL1β, which are required for expanding IL-17-producing T cells through I-MDSCs, a distinct MDSC subset that is dependent on GM-CSF. 37 Ripk3 activity is mediated by TLR4. 38 We ever used CD11b/Gr 1 double staining to detect the expression of MDSC in spleen and bone marrow of WT, Apc Min/+ , Apc Min/+ TLR4 −/− mice by flow cytometry.…”

RIPK3 inhibition prevents KRAS mutant p53 deficient lung tumor progression by impeding MDSCs

“…RIPK3 dependent ERK1/2 is a novel signaling pathway that accompanies pathogenic cell death or necroptosis that has been identified as a target for treating inflammatory diseases (8). RIPK3 signaling induces inflammatory cytokines in myeloid cells such as macrophages and MDSCs (9,10). We showed that RIPK3 signaling in MDSCs produces cytokines required to generate Th17 cells.…”

“…Receptor interacting protein kinases such as receptor interacting protein kinase 1 (RIPK1) and RIPK3 induce necroptotic cell death but also have an alternate function in signaling by inducing cytokines (8). We showed that targeting MDSCs by inhibiting RIPK3 signaling, changes the ability of MDSCs to promote Th17 cells in intestinal cancer (9). These results also showed that RIPK3 induced cytokines in MDSCs could support their suppressive function.…”