A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells.
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.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Meromit
M
Singer
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.
Chao
C
Wang
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Le
L
Cong
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.
Nemanja D
ND
Marjanovic
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Monika S
MS
Kowalczyk
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.
Huiyuan
H
Zhang
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jackson
J
Nyman
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.
Kaori
K
Sakuishi
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.
Sema
S
Kurtulus
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
David
D
Gennert
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.
Junrong
J
Xia
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
John Y H
JYH
Kwon
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.
James
J
Nevin
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Rebecca H
RH
Herbst
Institute for Computational Medicine and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Itai
I
Yanai
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Orit
O
Rozenblatt-Rosen
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.
Vijay K
VK
Kuchroo
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.
Aviv
A
Regev
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.
Ana C
AC
Anderson
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D064113:CRISPR-Cas Systems; D063646:Carcinogenesis / Q000235:genetics / Q000276:immunology; D005260:Female; D050990:GATA3 Transcription Factor / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology*; D008545:Melanoma / Q000276:immunology / Q000503:physiopathology; D008668:Metallothionein / Q000172:deficiency; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
D050990:GATA3 Transcription Factor; D008668:Metallothionein
CD8; CRISPR/Cas9; Gata-3; T cell; TILs; cancer; dysfunction; exhaustion; metallothioneins; single-cell; tumor; zinc