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

Although adoptive T cell therapy has shown remarkable clinical efficacy in hematological 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.

尽管过继性T细胞疗法（adoptive T cell therapy）在血液系统恶性肿瘤中已展现出卓越的临床疗效，但其在对抗实体瘤方面的应用成效却始终受限。本研究证实，T细胞内PTPN2的缺失可强化癌症免疫监视功能，并提升过继转移的肿瘤特异性T细胞的治疗效果。T细胞特异性PTPN2缺陷可阻止携带有肿瘤抑制基因p53杂合突变的老年小鼠体内肿瘤的形成。将PTPN2缺陷型CD8+ T细胞过继移植后，可显著抑制荷瘤小鼠的乳腺肿瘤发生。此外，在表达靶向癌蛋白HER-2的嵌合抗原受体（CAR）的T细胞中缺失PTPN2，可增强Src家族激酶LCK的活化水平以及细胞因子诱导的STAT-5信号通路活性，进而同时强化CAR-T细胞的活化能力与向表达CXCL9/10的肿瘤组织的归巢能力，最终在体内彻底根除HER-2阳性乳腺肿瘤。本研究结果明确了PTPN2作为增强T细胞介导的抗肿瘤免疫以及抗实体瘤CAR-T细胞疗法潜在靶点的价值。