| First Author | Zhou C | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 499 |
| PubMed ID | 38216551 | Mgi Jnum | J:351184 |
| Mgi Id | MGI:7575199 | Doi | 10.1038/s41467-024-44779-1 |
| Citation | Zhou C, et al. (2024) Mutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death. Nat Commun 15(1):499 |
| abstractText | Mutant KRAS (KRAS(MUT)) 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 KRAS(MUT) cancers are sensitive to activation-induced cell death (AICD). circATXN7, an NF-kappaB-interacting circular RNA, governs T cell sensitivity to AICD by inactivating NF-kappaB. Mechanistically, histone lactylation derived from KRAS(MUT) tumor cell-produced lactic acid directly activates transcription of circATXN7, which binds to NF-kappaB 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. |
