Lynch et al. created a chimeric PD-1 receptor (chPD1) by replacing the inhibitory domains of PD-1 with the activating domains of CD3ζ and Dap10 or CD28. Adoptively transferred chPD1-Dap10 T cells showed superior anti-tumor efficacy in immunocompetent, lymphoma-bearing mice compared with chPD1-CD28 T cell therapy, likely due to their preferential cytokine profile and differentiation phenotype.
Adoptive transfer of T cells is a promising cancer therapy and expression of chimeric antigen receptors can enhance tumor recognition and T cell effector functions. The PD1 receptor is a prospective target for a chimeric antigen receptor because PD1 ligands are expressed on many cancer types, including lymphoma. Therefore, we developed a murine chimeric PD1 receptor (chPD1) consisting of the PD1 extracellular domain fused to the cytoplasmic domain of CD3 zeta. Additionally, chimeric antigen receptor therapies utilize various costimulatory domains to enhance efficacy. Thus, the inclusion of a Dap10 or CD28 costimulatory domain in the chPD1 receptor was compared to determine which domain induced optimal anti-tumor immunity in a mouse model of lymphoma. ChPD1 T cells secreted proinflammatory cytokines and lysed RMA lymphoma cells. Adoptive transfer of chPD1 T cells significantly reduced established tumors and led to tumor free survival in lymphoma-bearing mice. When comparing chPD1 receptors containing a Dap10 or CD28 domain, both receptors induced secretion of proinflammatory cytokines, however chPD1-CD28 T cells also secreted anti-inflammatory cytokines whereas chPD1-Dap10 T cells did not. Additionally, chPD1-Dap10 induced a central memory T cell phenotype compared to chPD1-CD28 which induced an effector memory phenotype. ChPD1-Dap10 T cells also had enhanced in vivo persistence and anti-tumor efficacy compared to chPD1-CD28 T cells. Therefore, adoptive transfer of chPD1 T cells could be a novel therapy for lymphoma and inclusion of the Dap10 costimulatory domain in chimeric antigen receptors may induce a preferential cytokine profile and T cell differentiation phenotype for anti-tumor therapies. This article is protected by copyright. All rights reserved.