A distinct gene module uncouples dysfunction from activation in tumor-infiltrating T cells (part 2)

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 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. Overall design: CD8 TILs sorted on PD1 and Tim3 to subpopulations were analyzed from two batches: batch 1: 2 WT and 2 MTKO mice , batch 2: 2 WT and 3 MTKO mice.

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Singer M, Wang C, Cong L, Marjanovic ND, Kowalczyk MS, Zhang H, Nyman J, Sakuishi K, Kurtulus S, Gennert D, Xia J, Kwon JYH, Nevin J, Herbst RH, Yanai I, Rozenblatt-Rosen O, Kuchroo VK, Regev A, Anderson AC