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.