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A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells.

Cell | Sep 8, 2016

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.

Pubmed ID: 27610572 RIS Download

Mesh terms: Animals | CD8-Positive T-Lymphocytes | CRISPR-Cas Systems | Carcinogenesis | Female | GATA3 Transcription Factor | Gene Expression Profiling | Gene Expression Regulation, Neoplastic | Humans | Lymphocyte Activation | Lymphocytes, Tumor-Infiltrating | Melanoma | Metallothionein | Mice | Mice, Inbred BALB C | Mice, Inbred C57BL

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Associated grants

  • Agency: NCI NIH HHS, Id: U24 CA180922
  • Agency: NINDS NIH HHS, Id: R01 NS045937
  • Agency: NCI NIH HHS, Id: P30 CA014051
  • Agency: NCI NIH HHS, Id: R01 CA187975
  • Agency: Howard Hughes Medical Institute, Id: P01 AI045757
  • Agency: NIAID NIH HHS, Id: P01 AI073748
  • Agency: NIAID NIH HHS, Id: RM1 HG006193
  • Agency: HHMI, Id:
  • Agency: NHGRI NIH HHS, Id:

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