2026-07-31 ロックフェラー大学
＜関連情報＞
- https://www.rockefeller.edu/news/40223-mapping-how-metabolism-rewires-protein-function-in-cancer/
- https://www.biorxiv.org/content/10.64898/2026.03.04.709614v1
慢性抗原誘発性ヒトT細胞機能障害の翻訳後調節マップ A post-translational regulatory map of chronic antigen-driven human T cell dysfunction
Hiroyuki Kojima, Charlotte R. Wayne, Luis F. Somarribas Patterson, Henry Sanford, Tzu-Jou Chen, Ya-Hui Lin, Joshua D. Schoenfeld, Lisa H. F. McGary, Yan-Ting Chen, Korbinian N. Kropp, Beatrice Zhang, Jahan Rahman, Tiffany L. Zhang, Nathalie Ropek, Cameron Roberts, Yuxi Ai, Kartikeya M. Menon, A. Ari Hakimi, Jiankun Lyu, Christopher A. Klebanoff, Omar Abdel-Wahab, Santosha A. Vardhana, Ekaterina V. Vinogradova
bioRxiv Posted: March 06, 2026
DOI:https://doi.org/10.64898/2026.03.04.709614
SUMMARY
T cells exposed to persistent antigen in the context of chronic viral infections or cancer lose self-renewal and cytotoxic capacity. Several transcriptional, epigenetic, and metabolic drivers of this process have been identified. However, the post-transcriptional regulatory mechanisms influencing the proteome of dysfunctional T cells are not well understood. Here we present a time-resolved molecular landscape of human T cells during the development of chronic antigen-driven dysfunction. Persistent T cell receptor stimulation significantly remodeled the proteome, including changes in canonical T cell exhaustion-associated proteins and proteins related to mitochondrial function, redox homeostasis, nucleotide metabolism, and cell-cycle progression. Dysfunctional T cells displayed activation of stress response pathways that were recapitulated in vivo; targeting these pathways altered the cytotoxic capacity of T cells during persistent tumor exposure. Our comprehensive proteomic resource reveals unique post-transcriptional changes in dysfunctional T cells and lays the groundwork for novel cysteine-directed therapeutics to enhance cancer immunotherapy.
