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.
Highlights
T cell–directed immunotherapy has delivered remarkable therapeutic benefits in cancer patients
We sought to determine the effect of PTPN22 deficiency on the capacity of CTLs to directly mediate target cell killing in response to strong and weak tumor-associated antigens (TAAs)
Previous studies have shown that T cell receptors (TCR) triggering influences expression of inhibitory phosphatases [15]; it was of interest to determine the levels of PTPN22 following stimulation of OT-1 T cells with weak and strong agonist peptides
Summary
T cell–directed immunotherapy has delivered remarkable therapeutic benefits in cancer patients. A key consideration for ACT approaches to cancer therapy is to determine which T cell phenotype provides optimal long-lived protection. Upon transfer to naive recipient mice, very low numbers of long-lived Ptpn22–/– memory T cells provided enhanced protection from tumor challenge, as compared with control cells. Ptpn22–/–, but not control, memory phenotype T cell ACT could completely protect mice from low-affinity antigen-bearing tumors when transferred to hosts 2–4 weeks prior to tumor implantation. Together, these experiments have determined that deletion of PTPN22 represents a rational approach to enhance the functional capacity of both short-lived effector and long-lived memory T cells in antitumor immunity
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