Leeds Institute of Medical Research at St. James's, University of Leeds, Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, United Kingdom.
Institute of Immunology and Infection Research, University of Edinburgh, Ashworth Laboratories, Edinburgh, United Kingdom.
JCI Insight. 2019 Jul 23;5(16):127847. doi: 10.1172/jci.insight.127847.
Adoptive T cell therapy (ACT) has been established as an efficacious methodology for the treatment of cancer. Identifying targets to enhance the antigen recognition, functional capacity and longevity of T cells has the potential to broaden the applicability of these approaches in the clinic. We previously reported that targeting expression of phosphotyrosine phosphatase, non-receptor type (PTPN) 22 in effector CD8+ T cells enhances the efficacy of ACT for tumor clearance in mice. In the current work, we demonstrate that, upon ACT, PTPN22-deficient effector CD8+ T cells afford greater protection against tumors expressing very low affinity antigen, but do not survive long-term in vivo. Persistence of CD8+ T cells following tumor clearance is improved by ACT of memory phenotype cells that have a distinct metabolic phenotype as compared to effector T cells. Importantly, PTPN22-deficient T cells have comparable capacity to form long-lived memory cells in vivo but enhanced anti-tumor activity in vivo and effector responses ex vivo. These findings provide key insight into the regulation of effector and memory T cell responses in vivo, and indicate that PTPN22 is a rationale target to improve ACT for cancer.
过继性 T 细胞疗法 (ACT) 已被确立为治疗癌症的有效方法。确定增强 T 细胞抗原识别、功能能力和寿命的靶点有可能拓宽这些方法在临床上的适用性。我们之前报道过，靶向表达磷酸酪氨酸磷酸酶，非受体型 (PTPN) 22 在效应 CD8+T 细胞中可增强 ACT 对清除小鼠肿瘤的功效。在当前的工作中，我们证明，在 ACT 后，缺乏 PTPN22 的效应 CD8+T 细胞在对抗表达极低亲和力抗原的肿瘤时提供了更大的保护，但在体内不能长期存活。与效应 T 细胞相比，记忆表型细胞具有独特的代谢表型，其 ACT 可改善肿瘤清除后 CD8+T 细胞的持久性。重要的是，缺乏 PTPN22 的 T 细胞在体内具有形成长期记忆细胞的可比能力，但在体内具有增强的抗肿瘤活性和体外效应反应。这些发现为体内调节效应和记忆 T 细胞反应提供了重要的见解，并表明 PTPN22 是改善癌症 ACT 的合理靶点。
