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Department of Microbiology and Carter Immunology Center, University of Virginia, Charlottesville, VA 22908
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 tyrosinase369–376 or
gp100209–217 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-
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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