A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells
Name
nihms813125.pdf
Size
3.17 MB
Format
Adobe PDF
Checksum (MD5)
810756f2c361e8ccb8901da138d5baee
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.
Date Issued
September 2016
Journal
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
Abstract
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.
MIT Department
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 MIT
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/J.CELL.2016.08.052
