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Nat Immunol. 2019 Oct;20(10):1335-1347. doi: 10.1038/s41590-019-0480-4. Epub 2019 Sep 16.

PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity.

Author information

1
Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
2
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
3
Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
4
Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
5
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
6
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
7
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. nick.haining@merck.com.
8
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. nick.haining@merck.com.
9
Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. Arlene_Sharpe@hms.harvard.edu.
10
Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. Arlene_Sharpe@hms.harvard.edu.
11
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. Arlene_Sharpe@hms.harvard.edu.

Abstract

CD8+ T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6+ progenitor exhausted and Tim-3+ terminally exhausted subpopulations through unknown mechanisms. Here we establish the phosphatase PTPN2 as a new regulator of the differentiation of the terminally exhausted subpopulation that functions by attenuating type 1 interferon signaling. Deletion of Ptpn2 in CD8+ T cells increased the generation, proliferative capacity and cytotoxicity of Tim-3+ cells without altering Slamf6+ numbers during lymphocytic choriomeningitis virus clone 13 infection. Likewise, Ptpn2 deletion in CD8+ T cells enhanced Tim-3+ anti-tumor responses and improved tumor control. Deletion of Ptpn2 throughout the immune system resulted in MC38 tumor clearance and improved programmed cell death-1 checkpoint blockade responses to B16 tumors. Our results indicate that increasing the number of cytotoxic Tim-3+CD8+ T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target.

PMID:
31527834
PMCID:
PMC6754306
[Available on 2020-03-16]
DOI:
10.1038/s41590-019-0480-4

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