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EMBO J. 2020 Jan 15;39(2):e103637. doi: 10.15252/embj.2019103637. Epub 2019 Dec 5.

PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours.

Author information

1
Monash Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia.
2
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia.
3
Peter MacCallum Cancer Centre, Melbourne, Vic., Australia.
4
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic., Australia.
5
Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Vic., Australia.
6
Peter Doherty Institute for Infection and Immunity, Melbourne, Vic., Australia.
7
Telethon Kids Institute, University of Western Australia, Perth, WA, Australia.
8
Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Purdue University, West Lafayette, IN, USA.

Abstract

Although adoptive T-cell therapy has shown remarkable clinical efficacy in haematological malignancies, its success in combating solid tumours has been limited. Here, we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour-specific T cells. T-cell-specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53. Adoptive transfer of PTPN2-deficient CD8+ T cells markedly repressed tumour formation in mice bearing mammary tumours. Moreover, PTPN2 deletion in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER-2 increased the activation of the Src family kinase LCK and cytokine-induced STAT-5 signalling, thereby enhancing both CAR T-cell activation and homing to CXCL9/10-expressing tumours to eradicate HER-2+ mammary tumours in vivo. Our findings define PTPN2 as a target for bolstering T-cell-mediated anti-tumour immunity and CAR T-cell therapy against solid tumours.

KEYWORDS:

CAR T cells; STAT-5 signalling; TCR signalling; adoptive T-cell therapy; protein tyrosine phosphatase N2

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