Kavli Affiliate: Ekaterina V. Vinogradova
| Authors: 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 Menon, A. Ari Hakimi, Jiankun Lyu, Christopher A. Klebanoff, Omar Abdel-Wahab, Santosha A Vardhana and Ekaterina V Vinogradova
| 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.