Deletion of PTPN22 improves effector and memory CD8+ T cell responses to tumors
Rebecca J. Brownlie, David Wright, Rose Zamoyska, Robert J. Salmond
Rebecca J. Brownlie, David Wright, Rose Zamoyska, Robert J. Salmond
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Research Article Immunology

Deletion of PTPN22 improves effector and memory CD8+ T cell responses to tumors

Abstract

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, nonreceptor type 22 (PTPN22) 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 afforded greater protection against tumors expressing very low-affinity antigen but did not survive long term in vivo. Persistence of CD8+ T cells following tumor clearance was improved by ACT of memory phenotype cells that have a distinct metabolic phenotype, as compared with effector T cells. Importantly, PTPN22-deficient T cells have comparable capacity to form long-lived memory cells in vivo but enhanced antitumor activity in vivo and effector responses ex vivo. These findings provide key insights into the regulation of effector and memory T cell responses in vivo and indicate that PTPN22 is a rational target to improve ACT for cancer.

Authors

Rebecca J. Brownlie, David Wright, Rose Zamoyska, Robert J. Salmond

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Figure 6

PTPN22-deficient memory T cells prevent growth of tumors expressing weak antigen.

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PTPN22-deficient memory T cells prevent growth of tumors expressing weak...
(A) Scheme of experimental design. (B) Groups of C57BL/6J hosts were injected with 10 × 106 in vitro–generated control or Ptpn22–/– memory cells i.v. on day 0. On day 24, 1 × 106 EL4 cells loaded with T4 peptide were injected i.v. Tumor growth was monitored by caliper measurement, as shown for individual mice from 1 experiment (B), and tumor weight was measured at the end of the experiment (day 9 after EL4-T4 injection, when tumors in control mice reached a maximum-allowed diameter of 15 mm) (C). Each dot represents an individual mouse from 2 repeated experiments (C). ****P < 0.0001, as determined by 1-way ANOVA with Tukey’s multiple comparison test. (D) Groups of C57BL/6J hosts (n = 7/group) were injected with 10 × 106 in vitro–generated control or Ptpn22–/– memory cells i.v. on day 0. Fourteen days after T cell ACT, 1 × 106 EL4 cells loaded with T4 peptide were injected s.c. Tumor growth was monitored by caliper measurement at least 2 times a week for up 90 days after EL4-T4 injection. When tumor diameter exceeded 10 mm, mice were removed from the study. ***P < 0.0001, as determined by χ2 and log-rank test. (E and F) LNs and spleens were removed from all mice that had received Ptpn22–/– T memory cells at the end of the study (day 90 after EL4-T4 injection) and assessed for the presence of transferred T cells by FACS. Representative dot plots shows the percentage of Ptpn22–/– T memory cells (CD8+CD45.1+CD45.2+) and expression of CD62L and CD44. (F) Dots on the corresponding graphs represent values from individual animals.