By crossing T cell-specific-PTPN2-null mice onto the p53 tumor suppressor heterozygous background, Wiede et al. inhibited tumorigenesis without inciting inflammation. PTPN2-T cell-deficiency impeded tumor growth in mouse melanoma and breast cancer models, boosting effector T cell function, but not reducing Tregs. Adoptive transfer of PTPN2-null CD8+ T cells inhibited mammary tumor formation. PTPN2-silencing in HER-2 oncoprotein-specific CAR T cells induced LCK and cytokine-induced STAT-5 signaling to promote CXCR3hi CAR T cell homing to, repression of, and control of CXCL9/10+HER-2+ mammary tumors.
Contributed by Paula Hochman
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.
Author Info: (1) Monash Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Austral
Author Info: (1) Monash Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia. Peter MacCallum Cancer Centre, Melbourne, Vic., Australia. (2) Peter MacCallum Cancer Centre, Melbourne, Vic., Australia. (3) Peter MacCallum Cancer Centre, Melbourne, Vic., Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic., Australia. (4) Monash Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia. Peter MacCallum Cancer Centre, Melbourne, Vic., Australia. (5) Peter MacCallum Cancer Centre, Melbourne, Vic., Australia. Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Vic., Australia. Peter Doherty Institute for Infection and Immunity, Melbourne, Vic., Australia. (6) Monash Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia. (7) Monash Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia. Peter MacCallum Cancer Centre, Melbourne, Vic., Australia. (8) Peter MacCallum Cancer Centre, Melbourne, Vic., Australia. (9) Peter MacCallum Cancer Centre, Melbourne, Vic., Australia. (10) Peter MacCallum Cancer Centre, Melbourne, Vic., Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic., Australia. (11) Peter MacCallum Cancer Centre, Melbourne, Vic., Australia. (12) Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Vic., Australia. Peter Doherty Institute for Infection and Immunity, Melbourne, Vic., Australia. (13) Telethon Kids Institute, University of Western Australia, Perth, WA, Australia. (14) Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Purdue University, West Lafayette, IN, USA. (15) Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Purdue University, West Lafayette, IN, USA. (16) Peter MacCallum Cancer Centre, Melbourne, Vic., Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic., Australia. (17) Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Vic., Australia. Peter Doherty Institute for Infection and Immunity, Melbourne, Vic., Australia. (18) Peter MacCallum Cancer Centre, Melbourne, Vic., Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic., Australia. (19) Monash Biomedicine Discovery Institute, Monash University, Clayton, Vic., Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia. Peter MacCallum Cancer Centre, Melbourne, Vic., Australia.
