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

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 () and Chi Chun Wong ()
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Qiming Zhou: The Chinese University of Hong Kong
Yao Peng: The Chinese University of Hong Kong
Fenfen Ji: The Chinese University of Hong Kong
Huarong Chen: 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
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

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39571-6

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