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Singer, Meromit; Wang, Chao; Cong, Le; Marjanovic, Nemanja D.; Kowalczyk, Monika S.; Zhang, Huiyuan; Nyman, Jackson; Sakuishi, Kaori; Kurtulus, Sema; Gennert, David; Xia, Junrong; Kwon, John Y.H.; Nevin, James; Herbst, Rebecca H.; Yanai, Itai; Rozenblatt-Rosen, Orit; Kuchroo, Vijay K.; Regev, Aviv; Anderson, Ana C.
Cell, 09/2016, Volume: 166, Issue: 6Journal Article
Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8+ tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and we use CRISPR-Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8+ TILs. Our results open novel avenues for targeting dysfunctional T cell states while leaving activation programs intact. Display omitted •Distinct gene modules for T cell dysfunction and activation can be uncoupled•Single-cell profiling of CD8 TILs shows that these modules are exclusive•Metallothioneins, zinc regulators, promote T cell dysfunction•CRISPR-Cas9 targeting shows Gata-3, a zinc-finger TF, promotes dysfunction Single-cell profiling of tumor-infiltrating lymphocytes identifies critical regulators of T cell dysfunction in cancer, opening new avenues for targeting dysfunctional T cell states while leaving activation programs intact.
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