title: CD8 alpha coreceptor to improve TCR gene transfer to treat melanoma: down-regulation of tumor-specific production of IL-4, IL-5, and IL-10.
abstract: Therapeutic success of TCR gene transfer to treat tumors depends on the ability of redirected T cells to become activated upon tumor recognition in vivo. Help provided by tumor-specific Th1 cells is reported to relieve T cells from an anergized state and to induce tumor regression. We recently demonstrated the ability to generate melanoma-specific Th1 cells by genetic introduction of both a CD8-dependent TCR and the CD8alpha coreceptor into CD4+ T cells. In this study, we analyzed a TCR that binds Ag independently of CD8, a property generally preferred to induce tumor-specific T cell responses, and addressed the contribution of CD8alpha following introduction into TCR-transduced CD4+ T cells. To this end, primary human CD4+ T cells were gene transferred with a high-avidity TCR, and were shown not only to bind peptide/MHC class I, but also to effectively kill Ag-positive tumor cells in the absence of CD8alpha. The introduction of CD8alpha up-regulates the tumor-specific production of TNF-alpha and IL-2 to some extent, but significantly down-regulates production of IL-4, IL-5, and IL-10 in CD4+ T cells. The introduction of a mutated cysteine motif in CD8alpha, which prevents its binding to LCK and linker for activation of T cells, did not adversely affect expression and T cell cytotoxicity, but counteracted the CD8alpha-mediated down-regulation of IL-4 and IL-5, but not IL-10. In conclusion, CD8alpha down-regulates the production of major Th2-type cytokines, in part mediated by LCK and/or linker for activation of T cells, and may induce differentiation of tumor-specific Th1 cells, which makes this coreceptor an interesting candidate to improve the clinical potential of TCR gene transfer to treat cancer.
authors.affiliation: Laboratory of Tumor Immunology, Unit of Clinical and Tumor Immunology, Department of Medical Oncology, Erasmus Medisch Centrum (MC)-Daniel den Hoed Cancer Center, 3008 AE Rotterdam, The Netherlands.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Willemsen
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Sebestyén
authors.forename: Cees
authors.initials: C
authors.lastname: Ronteltap
authors.forename: Cor
authors.initials: C
authors.lastname: Berrevoets
authors.forename: Joost
authors.initials: J
authors.lastname: Drexhage
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D016827:CD8 Antigens / Q000235:genetics* / Q000502:physiology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D003545:Cysteine / Q000235:genetics; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D018014:Gene Transfer Techniques; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015848:Interleukin-5 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods; D058951:gp100 Melanoma Antigen
chemical_list: D016827:CD8 Antigens; C431698:CD8alpha antigen; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D015848:Interleukin-5; D008562:Membrane Glycoproteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D058951:gp100 Melanoma Antigen; D016753:Interleukin-10; D015847:Interleukin-4; D003545:Cysteine