the cd3-zeta chimeric antigen receptor overcomes tcr hypo-responsiveness of human terminal late-stage t cellscd3-zeta嵌合抗原受体克服了tcr hypo-responsiveness人类终端后期的t细胞.pdfVIP

The CD3-Zeta Chimeric Antigen Receptor Overcomes TCR Hypo-Responsiveness of Human Terminal Late- Stage T Cells 1,4 . 1. 2 3 1 Gunter Rappl * , Tobias Riet , Sabine Awerkiew , Annette Schmidt , Andreas A. Hombach , Herbert Pfister2,4, Hinrich Abken1,4 1Tumor Genetics, Dept. I Internal Medicine, University of Cologne, Cologne, Germany, 2 Institute for Virology, University of Cologne, Cologne, Germany, 3 Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany, 4 Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany Abstract Adoptive therapy of malignant diseases with tumor-specific cytotoxic T cells showed remarkable efficacy in recent trials. Repetitive T cell receptor (TCR) engagement of target antigen, however, inevitably ends up in hypo-responsive cells with terminally differentiated KLRG-1+ CD57+ CD72 phenotype limiting their therapeutic efficacy. We here revealed that hypo- responsiveness of CMV-specific late-stage CD8+ T cells is due to reduced TCR synapse formation compared to younger cells. Membrane anchoring of TCR components contributes to T cell hypo-responsiveness since dislocation of galectin-3 from the synapse by swainsonine restored both TCR synapse formation and T cell response. Transgenic expression of a CD3-zeta signaling chimeric antigen receptor (CAR) recovered hypo-responsive T cells to full effector functions indicating that the defect is restricted to TCR membrane components while synapse formation of the transgenic CAR was not blocked. CAR engineered late-stage T cells released cytokines and mediated redirected cytotoxicity as efficiently as younger effector T cells. Our data provide a rationale for TCR independent, CAR mediated activation in the adoptive cell therapy to