The role of myeloid cell SIRT1 in regulation of intestinal inflammation, anti-tumor immunity, and tumorigenesis

Authors

• MJ Payea
• S Dar
• C Belair
• JM Martindale
• RB Munk
• M Maragkakis

Abstract

Immune cells, which are primarily in the gut, interact extensively with gut epithelial cells and gut microbiota to maintain gut and immune homeostasis. Disruption of this intricate interplay leads to numerous human diseases, including inflammatory bowel disease and intestinal/colorectal cancers. We have previously shown that specific deletion of sirtuin 1 (SIRT1), a highly conserved mammalian NAD+-dependent protein deacetylase, in myeloid cells activates NF-kB, particularly in macrophages, resulting in increased systemic inflammation after high-fat diet feeding. In this study, we aim to explore the possible impacts of myeloid cell SIRT1 on gut tissue homeostasis by challenging mice with specific deletion of SIRT1 in myeloid cells, My-SIRT1 KO mice, with different intestinal disease models. Our preliminary observations showed that My-SIRT1 KO mice were hypersensitive to morbidity and tissue damage in the dextran sodium sulfate (DSS)-induced colitis model. However, when bred into the Apcmin+/- background, a genetic intestinal tumor model, these mice displayed significant suppression of late-stage colon tumor growth, compared to control mice. Furthermore, in a syngeneic colon cancer model using MC38 mouse colon cancer cells, although subcutaneously grafted MC38 tumors on My-SIRT1 KO mice grew significantly bigger than those on control mice, they were highly sensitive to anti-PD1 antibody-induced tumor suppression. Our observations suggest that SIRT1 deficiency in myeloid cells may activate pro-inflammatory pathways and increase their survival/proliferation, leading to enhanced systemic anti-tumor immunity. We are currently working to test this hypothesis.

Scientific Focus Area: Cancer Biology

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