title: CD4+CD25- T cells transduced to express MHC class I-restricted epitope-specific TCR synthesize Th1 cytokines and exhibit MHC class I-restricted cytolytic effector function in a human melanoma model.
abstract: Cytolytic T cell-centric active specific and adoptive immunotherapeutic approaches might benefit from the simultaneous engagement of CD4(+) T cells. Considering the difficulties in simultaneously engaging CD4(+) and CD8(+) T cells in tumor immunotherapy, especially in an Ag-specific manner, redirecting CD4(+) T cells to MHC class I-restricted epitopes through engineered expression of MHC class I-restricted epitope-specific TCRs in CD4(+) T cells has emerged as a strategic consideration. Such TCR-engineered CD4(+) T cells have been shown to be capable of synthesizing cytokines as well as lysing target cells. We have conducted a critical examination of functional characteristics of CD4(+) T cells engineered to express the alpha- and beta-chains of a high functional avidity TCR specific for the melanoma epitope, MART-1(27-35), as a prototypic human tumor Ag system. We found that unpolarized CD4(+)CD25(-) T cells engineered to express the MART-1(27-35) TCR selectively synthesize Th1 cytokines and exhibit a potent Ag-specific lytic granule exocytosis-mediated cytolytic effector function of comparable efficacy to that of CD8(+) CTL. Such TCR engineered CD4(+) T cells, therefore, might be useful in clinical immunotherapy.
authors.affiliation: Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA. arvindac@yahoo.com
authors.forename: Arvind
authors.initials: A
authors.lastname: Chhabra
authors.forename: Lili
authors.initials: L
authors.lastname: Yang
authors.forename: Pin
authors.initials: P
authors.lastname: Wang
authors.forename: Begoña
authors.initials: B
authors.lastname: Comin-Anduix
authors.forename: Raja
authors.initials: R
authors.lastname: Das
authors.forename: Nitya G
authors.initials: NG
authors.lastname: Chakraborty
authors.forename: Swagatam
authors.initials: S
authors.lastname: Ray
authors.forename: Shikhar
authors.initials: S
authors.lastname: Mehrotra
authors.forename: Haiguang
authors.initials: H
authors.lastname: Yang
authors.forename: Cinnamon L
authors.initials: CL
authors.lastname: Hardee
authors.forename: Roger
authors.initials: R
authors.lastname: Hollis
authors.forename: David I
authors.initials: DI
authors.lastname: Dorsky
authors.forename: Richard
authors.initials: R
authors.lastname: Koya
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kohn
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.forename: James S
authors.initials: JS
authors.lastname: Economou
authors.forename: David
authors.initials: D
authors.lastname: Baltimore
authors.forename: Bijay
authors.initials: B
authors.lastname: Mukherji
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism; D005822:Genetic Vectors; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D016207:Cytokines; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; C105787:MART-1-Melan-A(27-35) epitope; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell