title: Manipulation of avidity to improve effectiveness of adoptively transferred CD8(+) T cells for melanoma immunotherapy in human MHC class I-transgenic mice.
abstract: The adoptive transfer of tumor-reactive CD8(+) T cells into tumor-bearing hosts provides an attractive alternative to vaccination-based active immunotherapy of melanoma. The development of techniques that result in the preferential expansion of tumor-reactive T cells is therefore of great importance. In this study, we report the generation of HLA-A*0201-restricted CD8(+) T cell populations that recognize either tyrosinase(369-376) or gp100(209-217) from tolerant human class I MHC-transgenic mice by using single amino acid-substituted variant peptides. Low peptide concentration or restimulation with the parent peptide was used to enhance the functional avidity, defined by stimulation of IFN-gamma accumulation, and cross-reactivity of the resulting T cell populations. We found a direct correlation between the ability of a T cell population to respond in vitro to low concentrations of the precise peptide expressed on the tumor and its ability to delay the outgrowth of B16 melanoma after adoptive transfer. Surprisingly, we found that some T cells that exhibited high functional avidity and were effective in controlling tumor outgrowth exhibited low structural avidity, as judged by MHC-tetramer staining. Our results establish strategies for the development and selection of CD8(+) T cell populations that persist despite peripheral tolerance, and that can control melanoma outgrowth. Furthermore, they support the use of human MHC class I-transgenic mice as a preclinical model for developing effective immunotherapies that can be rapidly extended into therapeutic settings.
authors.affiliation: Department of Microbiology and Carter Immunology Center, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: T N
authors.initials: TN
authors.lastname: Bullock
authors.forename: D W
authors.initials: DW
authors.lastname: Mullins
authors.forename: T A
authors.initials: TA
authors.lastname: Colella
authors.forename: V H
authors.initials: VH
authors.lastname: Engelhard
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology / Q000637:transplantation*; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D005805:Genes, MHC Class I / Q000235:genetics*; D006183:H-2 Antigens / Q000235:genetics; D015234:HLA-A Antigens / Q000235:genetics; D015789:HLA-A2 Antigen; D064532:Histocompatibility Antigen H-2D; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D014442:Monophenol Monooxygenase / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D010455:Peptides / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology; D058951:gp100 Melanoma Antigen
chemical_list: D000951:Antigens, Neoplasm; D019013:CD40 Antigens; D006183:H-2 Antigens; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D064532:Histocompatibility Antigen H-2D; D008562:Membrane Glycoproteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D010455:Peptides; C548642:Pmel protein, mouse; D011948:Receptors, Antigen, T-Cell; D058951:gp100 Melanoma Antigen; D007371:Interferon-gamma; D014442:Monophenol Monooxygenase