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

作者：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^*

来源：Cell, 2016, 166(6): 1500-+.

DOI：10.1016/j.cell.2016.08.052

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.

• 出版日期2016-9-8