1. Academic Validation
  2. Ketogenesis Attenuates KLF5-Dependent Production of CXCL12 to Overcome the Immunosuppressive Tumor Microenvironment in Colorectal Cancer

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

  • Cancer Res. 2022 Apr 15;82(8):1575-1588. doi: 10.1158/0008-5472.CAN-21-2778.
Ruozheng Wei 1 2 Yuning Zhou 2 Chang Li 2 Piotr Rychahou 2 3 Shulin Zhang 2 4 William B Titlow 2 4 Greg Bauman 5 Yuanyuan Wu 2 Jinpeng Liu 2 Chi Wang 2 Heidi L Weiss 2 B Mark Evers 2 3 Qingding Wang 2 3
Affiliations

Affiliations

  • 1 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Markey Cancer Center, University of Kentucky, Lexington, Kentucky.
  • 3 Department of Surgery, University of Kentucky, Lexington, Kentucky.
  • 4 Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky.
  • 5 Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky.
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 TME is 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 β-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.

Significance: This study identifies ketogenesis as a critical regulator of the tumor microenvironment in colorectal Cancer and suggests the potential for ketogenic diets as a metabolic strategy to overcome immunosuppression and prolong survival. See related commentary by Montrose and Galluzzi, p. 1464.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-19994
    99.21%, KLF5 Inhibitor
    KLF