克拉斯
癌症研究
肿瘤微环境
结直肠癌
免疫系统
CD8型
CXCL1型
生物
免疫学
癌症
趋化因子
遗传学
作者
Qiming Zhou,Peng Yao,Fenfen Ji,Huarong Chen,Wei Kang,Lam-Shing Chan,Hongyan Gou,Yu‐Feng Lin,Pingmei Huang,Danyu Chen,Qinyao Wei,Hao Su,Cong Liang,Xiang Zhang,Jun Yu,Jun Yu
标识
DOI:10.1038/s41467-023-39571-6
摘要
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.
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