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Tumor microenvironment and transcriptional analysis of CD45+ leukocytes isolated from syngeneic MC38 tumors from mice fed ketogenic diet or control diet

ABSTRACT: Tumor microenvironment (TME) has a dynamic composition that affects targeted therapies for colorectal cancer (CRC). Cancer associated fibroblasts (CAFs) direct and induce infiltration of immunosuppressive cells through secreted cytokines such as CXCL12. Here, we show that decreased ketogenesis is a signature of CRCs and that an increase in ketogenesis, using a ketogenic diet (KD), decreases CXCL12 in CAFs, tumors, serum, livers, and lungs. Increase in ketogenesis results in the decreased expression of KLF5, which binds to the CXCL12 promoter and induces CXCL12 expression. KD decreases intratumoral accumulation of M2 macrophages and myeloid-derived suppressor cells (MDSCs), increases infiltration of NK and cytotoxic T cells and enhances the anticancer effects of PD-1 blockade in murine-derived CRCs. Moreover, an increase in ketogenesis inhibits CRC migration, invasion, and metastasis in vitro and in vivo. Importantly, our studies demonstrate that downregulation of de novo ketogenesis in the TME is a critical step in CRC progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE180110 | GEO | 2022/04/27

REPOSITORIES: GEO

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