Ketogenesis Attenuates KLF5-Dependent Production of CXCL12 to Overcome the Immunosuppressive Tumor Microenvironment in Colorectal Cancer

Ruozheng Wei, Yuning Zhou, Chang Li, Piotr Rychahou, Shulin Zhang, William B. Titlow, Greg Bauman, Yuanyuan Wu, Jinpeng Liu, Chi Wang, Heidi L. Weiss, B. Mark Evers, Qingding Wang

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The dynamic composition of the tumor microenvironment (TME) can markedly alter the response to targeted therapies for colorectal cancer. Cancer-associated fibroblasts (CAF) are major components of TMEs that can direct and induce infiltration of immunosuppressive cells through secreted cytokines such as CXCL12. Ketogenic diets (KD) can inhibit tumor growth and enhance the anticancer effects of immune checkpoint blockade. However, the role of ketogenesis on the immunosuppressive TMEis not known. Here, we show that decreased ketogenesis is a signature of colorectal cancer and that an increase in ketogenesis using a KD decreases CXCL12 production in tumors, serum, liver, and lungs. Moreover, increasing ketogenesis by overexpression of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) or treatment with the ketone body b-hydroxybutyrate markedly decreased expression of KLF5, which binds the CXCL12 promoter and induces CXCL12 expression in CAFs. KD decreased intratumoral accumulation of immunosuppressive cells, increased infiltration of natural killer and cytotoxic T cells, and enhanced the anticancer effects of PD-1 blockade in murine-derived colorectal cancer. Furthermore, increasing ketogenesis inhibited colorectal cancer migration, invasion, and metastasis in vitro and in vivo. Overall, ketogenesis is downregulated in the colorectal cancer TME, and increased ketogenesis represses KLF5-dependent CXCL12 expression to improve the immunosuppressive TME, which leads to the enhanced efficacy of immunotherapy and reduced metastasis. Importantly, this work demonstrates that downregulation of de novo ketogenesis in the TME is a critical step in colorectal cancer progression.

Original languageEnglish
Pages (from-to)1575-1588
Number of pages14
JournalCancer Research
Volume82
Issue number8
DOIs
StatePublished - Apr 15 2022

Bibliographical note

Funding Information:
P. Rychahou reports grants from NIH during the conduct of the study. B.M. Evers reports grants from National Institutes of Health and National Cancer Institute during the conduct of the study. No disclosures were reported by the other authors.

Funding Information:
This work was supported by National Institutes of Health grants R01 DK48498 and P30 CA177558 (to B.M. Evers), and a pilot grant from P20 GM121327 (to Q. Wang). The authors thank Donna Gilbreath for the article preparation; Dana Napier for tissue preparation, sectioning, and staining; Siva Gandhapudi and Jerry Woodward for Flow Cytometric analysis; the Flow Cytometry and Immune Monitoring core, OncoGenomics Shared Resource, Biospecimen Procurement and Translational Pathology, and Biostatistics and Bioinformatics shared resource facilities of the University of Kentucky Markey Cancer Center.

Publisher Copyright:
© 2022 American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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