Manipulation of avidity to improve effectiveness of adoptively transferred CD8+ T cells for melanoma immunotherapy in human MHC class I-transgenic mice

TNJ Bullock, DW Mullins, TA Colella… - The Journal of …, 2001 - journals.aai.org
The Journal of Immunology, 2001journals.aai.org
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 …
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-γ 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.
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