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 2

Ptpn22 does not effect the increased survival of memory versus effector CTLs in vivo.

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Ptpn22 does not effect the increased survival of memory versus effector ...
(A) On day 0, groups (n = 5) of C57BL/6 UbC-GFP hosts were injected with 1 × 106 EL4-N4 cells s.c. On day 6 after EL4 injection, groups of mice were injected with a mix of control and Ptpn22–/– effector CTLs or memory cells i.v. The recovery of these cells within LN and spleen populations was assessed 3 weeks after injection (day 27) by FACS, and they were identified as GFP-ve, CD8β+ T cells. Example dot plots are shown and dots on the graph represent individual animals. The proportion of donor CTLs recovered within the total CD8+ population was extremely low (<0.5%); in contrast, the proportion of memory cells was approximately 10% of total CD8+ T cells. (B and C) C57BL/6 UbC-GFP hosts (n = 10) were injected with 1 × 106 EL4-OVA cells s.c. (day = –6). After 6 days all mice were injected with an equal mix of control and Ptpn22–/– memory cells (5 × 106 of each) (day = 0), and groups of mice (n = 3/4) were assessed at day 8, day 14, and day 21 after memory cell injection by FACS. Example dot pots (from d = 21) are shown (B), and graphs (C) show the proportion of recovered control versus Ptpn22–/– memory cells within the LN and skin at the various time points. The ratio of control/Ptpn22–/– memory cells remains approximately 1:1 throughout the time course.