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Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer

Author

Listed:
  • Qiming Zhou

    (The Chinese University of Hong Kong)

  • Yao Peng

    (The Chinese University of Hong Kong
    Shenzhen University General Hospital)

  • Fenfen Ji

    (The Chinese University of Hong Kong)

  • Huarong Chen

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Wei Kang

    (The Chinese University of Hong Kong)

  • Lam-Shing Chan

    (The Chinese University of Hong Kong)

  • Hongyan Gou

    (The Chinese University of Hong Kong)

  • Yufeng Lin

    (The Chinese University of Hong Kong)

  • Pingmei Huang

    (The Chinese University of Hong Kong)

  • Danyu Chen

    (The Chinese University of Hong Kong)

  • Qinyao Wei

    (The Chinese University of Hong Kong)

  • Hao Su

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Cong Liang

    (Xiamen University)

  • Xiang Zhang

    (The Chinese University of Hong Kong)

  • Jun Yu

    (The Chinese University of Hong Kong)

  • Chi Chun Wong

    (The Chinese University of Hong Kong)

Abstract

KRAS is an important tumor intrinsic factor driving immune suppression in colorectal cancer (CRC). In this study, we demonstrate that SLC25A22 underlies mutant KRAS-induced immune suppression in CRC. In immunocompetent male mice and humanized male mice models, SLC25A22 knockout inhibits KRAS-mutant CRC tumor growth with reduced myeloid derived suppressor cells (MDSC) but increased CD8+ T-cells, implying the reversion of mutant KRAS-driven immunosuppression. Mechanistically, we find that SLC25A22 plays a central role in promoting asparagine, which binds and activates SRC phosphorylation. Asparagine-mediated SRC promotes ERK/ETS2 signaling, which drives CXCL1 transcription. Secreted CXCL1 functions as a chemoattractant for MDSC via CXCR2, leading to an immunosuppressive microenvironment. Targeting SLC25A22 or asparagine impairs KRAS-induced MDSC infiltration in CRC. Finally, we demonstrate that the targeting of SLC25A22 in combination with anti-PD1 therapy synergizes to inhibit MDSC and activate CD8+ T cells to suppress KRAS-mutant CRC growth in vivo. We thus identify a metabolic pathway that drives immunosuppression in KRAS-mutant CRC.

Suggested Citation

  • Qiming Zhou & Yao Peng & Fenfen Ji & Huarong Chen & Wei Kang & Lam-Shing Chan & Hongyan Gou & Yufeng Lin & Pingmei Huang & Danyu Chen & Qinyao Wei & Hao Su & Cong Liang & Xiang Zhang & Jun Yu & Chi Ch, 2023. "Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39571-6
    DOI: 10.1038/s41467-023-39571-6
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    References listed on IDEAS

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