Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer
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 KRA...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39571-6 |
| _version_ | 1797557910351380480 |
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| author | 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 Chun Wong |
| author_facet | 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 Chun Wong |
| author_sort | Qiming Zhou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:22:57Z |
| format | Article |
| id | doaj.art-ee931e2b1f17476088741b1651d761a4 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:22:57Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-ee931e2b1f17476088741b1651d761a42023-11-20T10:17:41ZengNature PortfolioNature Communications2041-17232023-08-0114111710.1038/s41467-023-39571-6Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancerQiming Zhou0Yao Peng1Fenfen Ji2Huarong Chen3Wei Kang4Lam-Shing Chan5Hongyan Gou6Yufeng Lin7Pingmei Huang8Danyu Chen9Qinyao Wei10Hao Su11Cong Liang12Xiang Zhang13Jun Yu14Chi Chun Wong15Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong KongInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong KongInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong KongInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong KongDepartment of Anatomical and Cellular Pathology, The Chinese University of Hong KongInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong KongInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong KongInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong KongInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong KongInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong KongInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong KongInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong KongState Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen UniversityInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong KongInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong KongInstitute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong KongAbstract 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.https://doi.org/10.1038/s41467-023-39571-6 |
| spellingShingle | 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 Chun Wong Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer Nature Communications |
| title | Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer |
| title_full | Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer |
| title_fullStr | Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer |
| title_full_unstemmed | Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer |
| title_short | Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer |
| title_sort | targeting of slc25a22 boosts the immunotherapeutic response in kras mutant colorectal cancer |
| url | https://doi.org/10.1038/s41467-023-39571-6 |
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