A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells
Author(s)
Singer, Meromit; Cong, Le; 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.; Anderson, Ana C.; Marjanovic, Nemanja; Regev, Aviv; Wang, Chao; ... Show more Show less![Thumbnail](/bitstream/handle/1721.1/116761/nihms813125.pdf.jpg?sequence=6&isAllowed=y)
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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.
Date issued
2016-09Department
Massachusetts Institute of Technology. Computational and Systems Biology Program; Massachusetts Institute of Technology. Department of Biology; Ludwig Center for Molecular Oncology (Massachusetts Institute of Technology); Koch Institute for Integrative Cancer Research at MITJournal
Cell
Publisher
Elsevier
Citation
Singer, Meromit et al. “A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells.” Cell 166, 6 (September 2016): 1500–1511 © 2016 Elsevier Inc
Version: Author's final manuscript
ISSN
0092-8674
1097-4172