TET2-mutant clonal hematopoiesis prevents T-cell exhaustion and suppresses cancer metastasis
Le, A. N. T.; Fujisawa, M.; Campo, G.; Nguyen, Y. T. M.; Nguyen, T. B.; Suma, S.; Suehara, Y.; Miura, F.; Araki, H.; Makishima, K.; Sakamoto, T.; Nakayama, M.; Oshima, M.; Kakiuchi, M.; Ishikawa, S.; Tanikawa, C.; Matsuda, K.; Saiki, R.; Ogawa, S.; Vanner, R. J.; Sakata-Yanagimoto, M.
Show abstract
Clonal hematopoiesis (CH) is widely regarded as a risk factor for age-associated disease, yet its influence on solid tumor progression remains poorly understood. Here, we uncover an unexpected tumor-suppressive role for TET2-mutant CH in solid tumors. Through an analysis of over 16,000 cancer patients, we demonstrate that TET2 mutations are associated with a significant reduction in metastatic burden. Mechanistically, we show that Tet2 deficiency prevents terminal exhaustion in CD8+ tumor-infiltrating lymphocytes (CD8+ TILs). This resistance is driven by DNA hypermethylation at regulatory elements of the transcription factor Tox, which prevents the induction of the terminal exhaustion program. Consequently, Tet2-deficient CD8+ TILs maintain stem-like, effector-competent states that mediate durable anti-tumor immunity and suppress metastatic outgrowth. Our findings establish TET2-mutant CH as a natural epigenetic constraint on T-cell exhaustion and uncover a mechanistically defined pathway with translational potential for enhancing anti-tumor immune responses.
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