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 5

PTPN22 deficiency improves T cell memory to tumors.

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PTPN22 deficiency improves T cell memory to tumors. (A) Scheme of experi...
(A) Scheme of experimental design. (B) Groups of C57BL/6-UbC-GFP hosts were injected with 1 × 106 EL4-N4 s.c. (day 0) before transfer of 5 × 106 control or Ptpn22–/– memory cells i.v. on day 5. On day 29, LNs were harvested from animals and the proportion of central memory (TCM: CD44+CD62L+) and effector memory (TEM: CD44+CD62L–) cells within the population of recovered memory cells (CD8β+GFP–) was quantified by FACS. (C and D) LN cells were also restimulated with varying concentrations of high-affinity (N4) and low-affinity (T4) peptide for 4 hours before intracellular staining for IFN-γ and TNF. Dots on the graphs show the frequency of IFN-γ+ and TNF+ cells within the population of recovered memory cells (day 29) (CD8β+GFP–). (E and F) Groups (n = 5) of C57BL6-UbC-GFP hosts were injected with 1 × 106 EL4-N4 s.c. before being injected with 5 × 106 control or Ptpn22–/– memory phenotype cells i.v. on day 5. On day 28, LNs and spleens were collected, and memory OT-1 cells were sorted by FACS (CD8β+, CD44+, GFP–). 1 × 104 sorted control or Ptpn22–/– cells were transferred i.v. into additional groups of C57BL/6-UbC-GFP hosts (day 28), which were injected with 1 × 106 EL4-N4 the subsequent day (day 29). Control mice received no memory cell ACT. Tumor growth was monitored by caliper measurement, as shown for individual mice from 1 experiment (E), and tumor weight was measured at the end of the experiment (day 12 after EL4-N4 injection). Each dot represents an individual mouse and represents data from 3 pooled experiments (F). *P < 0.05, **P < 0.01, ***P < 0.001, as determined by Student’s t test (B and D) or 1-way ANOVA with Tukey’s multiple comparisons test (F).