Mutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death

Chi Zhou, Wenxin Li, Zhenxing Liang, Xianrui Wu, Sijing Cheng, Jianhong Peng, Kaixuan Zeng, Weihao Li, Ping Lan, Xin Yang, Li Xiong, Ziwei Zeng, Xiaobin Zheng, Liang Huang, Wenhua Fan, Zhanzhen Liu, Yue Xing (), Liang Kang () and Huashan Liu ()
Additional contact information
Chi Zhou: Sun Yat-sen University Cancer Center
Wenxin Li: Sun Yat-sen University
Zhenxing Liang: Sun Yat-sen University
Xianrui Wu: Sun Yat-sen University
Sijing Cheng: Sun Yat-sen University
Jianhong Peng: Sun Yat-sen University Cancer Center
Kaixuan Zeng: the Second Affiliated Hospital of Xi’ an Jiaotong University
Weihao Li: Sun Yat-sen University Cancer Center
Ping Lan: Sun Yat-sen University
Xin Yang: Sun Yat-sen University
Li Xiong: Sun Yat-sen University
Ziwei Zeng: Sun Yat-sen University
Xiaobin Zheng: Sun Yat-sen University
Liang Huang: Sun Yat-sen University
Wenhua Fan: Sun Yat-sen University Cancer Center
Zhanzhen Liu: Sun Yat-sen University
Yue Xing: Sun Yat-Sen University
Liang Kang: Sun Yat-sen University
Huashan Liu: Sun Yat-sen University

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Mutant KRAS (KRASMUT) is often exploited by cancers to shape tumor immunity, but the underlying mechanisms are not fully understood. Here we report that tumor-specific cytotoxic T lymphocytes (CTLs) from KRASMUT cancers are sensitive to activation-induced cell death (AICD). circATXN7, an NF-κB-interacting circular RNA, governs T cell sensitivity to AICD by inactivating NF-κB. Mechanistically, histone lactylation derived from KRASMUT tumor cell-produced lactic acid directly activates transcription of circATXN7, which binds to NF-κB p65 subunit and masks the p65 nuclear localization signal motif, thereby sequestering it in the cytoplasm. Clinically, circATXN7 upregulation in tumor-specific CTLs correlates with adverse clinical outcomes and immunotherapeutic resistance. Genetic ablation of circAtxn7 in CD8+ T cells leads to mutant-selective tumor inhibition, while also increases anti-PD1 efficacy in multiple tumor models in female mice. Furthermore, targeting circATXN7 in adoptively transferred tumor-reactive CTLs improves their antitumor activities. These findings provide insight into how lymphocyte-expressed circRNAs contribute to T-cell fate decisions and anticancer immunotherapies.

Date: 2024
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DOI: 10.1038/s41467-024-44779-1

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