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

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

  • Nat Commun. 2024 Jan 12;15(1):499. doi: 10.1038/s41467-024-44779-1.
Chi Zhou # 1 2 3,  Wenxin Li # 4 5 6,  Zhenxing Liang # 4 5 6,  Xianrui Wu # 4 5 6,  Sijing Cheng 5,  Jianhong Peng 1 2 3,  Kaixuan Zeng 7,  Weihao Li 1 2 3,  Ping Lan 4 5 6,  Xin Yang 4 5 6,  Li Xiong 4 5 6,  Ziwei Zeng 4 5 6,  Xiaobin Zheng 4 5 6,  Liang Huang 4 5 6,  Wenhua Fan 1 2 3,  Zhanzhen Liu 4 5 6,  Yue Xing 8 9,  Liang Kang 10 11 12,  Huashan Liu 13 14 15 16
Affiliations

Affiliations

  • 1 Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 2 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 3 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 4 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 5 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 6 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 7 Precision Medical Research Institute, the Second Affiliated Hospital of Xi' an Jiaotong University, Xi'an, China.
  • 8 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. xingy28@mail.sysu.edu.cn.
  • 9 Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. xingy28@mail.sysu.edu.cn.
  • 10 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. kangl@mail.sysu.edu.cn.
  • 11 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. kangl@mail.sysu.edu.cn.
  • 12 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. kangl@mail.sysu.edu.cn.
  • 13 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. liuhshan@mail2.sysu.edu.cn.
  • 14 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. liuhshan@mail2.sysu.edu.cn.
  • 15 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. liuhshan@mail2.sysu.edu.cn.
  • 16 Guangdong Provincial Key Laboratory of Digestive Cancer Research, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China. liuhshan@mail2.sysu.edu.cn.
  • # Contributed equally.
PMID: 38216551 DOI: 10.1038/s41467-024-44779-1
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.

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