title: The CD3-zeta chimeric antigen receptor overcomes TCR Hypo-responsiveness of human terminal late-stage T cells.
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(+) CD7(-) 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 avoid hypo-responsiveness of late-stage T cells upon repetitive antigen encounter.
authors.affiliation: Tumor Genetics, Dept. I Internal Medicine, University of Cologne, Cologne, Germany. gunter.rappl@uni-koeln.de
authors.forename: Gunter
authors.initials: G
authors.lastname: Rappl
authors.forename: Tobias
authors.initials: T
authors.lastname: Riet
authors.forename: Sabine
authors.initials: S
authors.lastname: Awerkiew
authors.forename: Annette
authors.initials: A
authors.lastname: Schmidt
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Hombach
authors.forename: Herbert
authors.initials: H
authors.lastname: Pfister
authors.forename: Hinrich
authors.initials: H
authors.lastname: Abken
mesh_terms: D000328:Adult; D000368:Aged; D017252:CD3 Complex / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003586:Cytomegalovirus Infections / Q000097:blood / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics*; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D014162:Transfection; D055815:Young Adult
chemical_list: D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins