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

Meromit Singer ¹, Chao Wang ², Le Cong ¹, Nemanja D Marjanovic ³, Monika S Kowalczyk ¹, Huiyuan Zhang ², Jackson Nyman ¹, Kaori Sakuishi ², Sema Kurtulus ², David Gennert ¹, Junrong Xia ², John Y H Kwon ¹, James Nevin ², Rebecca H Herbst ¹, Itai Yanai ⁴, Orit Rozenblatt-Rosen ¹, Vijay K Kuchroo ⁵, Aviv Regev ⁶, Ana C Anderson ⁷

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biology, Koch Institute and Ludwig Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁴ Institute for Computational Medicine and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
⁵ Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: vkuchroo@evergrande.hms.harvard.edu.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biology, Koch Institute and Ludwig Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: aregev@broadinstitute.org.
⁷ Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: acanderson@partners.org.

PMID: 27610572
37 References
165 citations

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.

Keywords: CD8; CRISPR/Cas9; Gata-3; T cell; TILs; cancer; dysfunction; exhaustion; metallothioneins; single-cell; tumor; zinc.

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