期刊
CELL
卷 166, 期 6, 页码 1500-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2016.08.052
关键词
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资金
- NIH [R01NS045937, P01AI073748, R01CA187975, 5P01AI045757]
- American Cancer Society [RSG-11-057-01-LIB]
- Koch Institute Support (core) grant from the National Cancer Institute [P30-CA14051]
- Ludwig Center
- Klarman Cell Observatory at the Broad Institute
- HHMI
- Multiple Sclerosis Society of Canada
- Cancer Research Institute
- Charles A. King Trust Postdoctoral Research Fellowship Program, Bank of America, N.A
- Simeon J. Fortin Charitable Foundation, Bank of America, N.A
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.
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