Augmentation of CAR T-cell Trafficking and Antitumor Efficacy by Blocking Protein Kinase A Localization

摘要: Antitumor treatments based on the infusion of T cells expressing chimeric antigen receptors (CAR cells) are still relatively ineffective for solid tumors, due to presence immunosuppressive mediators [such as prostaglandin E2 (PGE2) and adenosine] poor T-cell trafficking. PGE2 adenosine activate protein kinase A (PKA), which then inhibits receptor (TCR) activation. This inhibition process requires PKA localize immune synapse via binding membrane ezrin. We generated CAR that expressed a small peptide called "regulatory subunit I anchoring disruptor" (RIAD) association with ezrin, thus blunting negative effects TCR After exposure or in vitro, CAR-RIAD showed increased signaling, released more cytokines, enhanced killing tumor compared cells. When injected into tumor-bearing mice, antitumor efficacy murine human was cells, resistance tumor-induced hypofunction infiltration established tumors. Subsequent vitro assays both mouse migrated efficiently than did response chemokine CXCL10 also had better adhesion various matrices. Thus, intracellular addition RIAD adoptively transferred augments their by increasing effector function improving trafficking sites. treatment strategy, therefore, shows potential clinical application treating Cancer Immunol Res; 4(6); 541-51. ©2016 AACR.