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Mutant KRAS drives immune evasion by sensitizing cytotoxic T-cells to activation-induced cell death in colorectal cancer

The roles of oncogenic KRAS in tumor immune evasion remain poorly understood. Here, mutant KRAS is identified as a key driver of tumor immune evasion in colorectal cancer (CRC). In human CRC specimens, a significant reduction in cytotoxic CD8+ T-cell tumor infiltration is found in patients with muta...

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Main Authors: Liu, Huashan (Author) , Liang, Zhenxing (Author) , Cheng, Sijing (Author) , Huang, Liang (Author) , Li, Wenxin (Author) , Zhou, Chi (Author) , Zheng, Xiaobin (Author) , Li, Shujuan (Author) , Zeng, Ziwei (Author) , Kang, Liang (Author)
Format: Article (Journal)
Language:English
Published: 04 January 2023
In: Advanced science
Year: 2023, Volume: 10, Issue: 6, Pages: 2203757
ISSN:2198-3844
DOI:10.1002/advs.202203757
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/advs.202203757
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/advs.202203757
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Author Notes:Huashan Liu, Zhenxing Liang, Sijing Cheng, Liang Huang, Wenxin Li, Chi Zhou, Xiaobin Zheng, Shujuan Li, Ziwei Zeng, Liang Kang
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Summary:The roles of oncogenic KRAS in tumor immune evasion remain poorly understood. Here, mutant KRAS is identified as a key driver of tumor immune evasion in colorectal cancer (CRC). In human CRC specimens, a significant reduction in cytotoxic CD8+ T-cell tumor infiltration is found in patients with mutant versus wild type KRAS. This phenomenon is confirmed by preclinical models of CRC, and further study showed KRAS mutant tumors exhibited poor response to anti-PD-1 and adoptive T-cell therapies. Mechanistic analysis revealed lactic acid derived from mutant KRAS-expressing tumor cells sensitized tumor-specific cytotoxic CD8+ T-cells to activation-induced cell death via NF-κB inactivation; this may underlie the inverse association between intratumoral cytotoxic CD8+ T-cells and KRAS mutation. Importantly, KRAS mutated tumor resistance to immunotherapies can be overcome by inhibiting KRAS or blocking lactic acid production. Together, this work suggests the KRAS-mediated immune program is an exploitable therapeutic approach for the treatment of patients with KRAS mutant CRC.
Item Description:Gesehen am 31.01.2024
Physical Description:Online Resource
ISSN:2198-3844
DOI:10.1002/advs.202203757

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