The Role of T Cell Avidity in Determining Tumor Immunity and Autoimmunity

Division Of Basic Sciences - Nci

Investigators

Abstract

Despite studies based on experimental models and clinical trials, the impact of T cell avidity on tumor immunity remains incompletely understood. We previously reported that sensitization of mice to a melanoma differentiation antigen, Tyrosinase-related protein-2 (TRP-2, dopachrome tautomerase, dct), results in weak T cell responses unless combined with GM-CSF and CTLA-4 blockade. In collaboration with Enzo Bronte (Univ. Padua), we subsequently established three T cell lines with specificity for the TRP-2(180-188) epitope, that differ in their avidity. We cloned the T cell antigen receptor genes and used them to make transgenic mice. This generated a unique model system as it consists of distinct T cell receptor genes with common antigenic specificity. The goal of this project is to use novel transgenic mouse models that we have developed at the NCI to test the hypothesis that T cell avidity is a critical determinant of tumor immunity. These studies will identify how T cell avidity correlates with tumor immunity and autoimmunity. We have recently characterized the intermediate avidity transgenic mouse line. These mice did not spontaneously develop depigmentation despite systemic expression of TRP-2 in the skin. Peripheral T cells from these TCR Tg mice exhibited a nave phenotype and proliferated in response to TRP-2 in vitro. In addition, transfer of in vitro-activated Tg T cells reduced B16 pulmonary tumor burden. We next sought to determine the in vivo responses of the Tg T cells to endogenous and tumor-derived TRP-2. Adoptive transfer of nave TCR Tg T cells into wild-type C57BL/6 mice, in combination with a TRP-2-pulsed dendritic cell vaccine, induced proliferation of the Tg T cells and resulted in migration of the Tg T cells into a subcutaneous B16 melanoma tumor. Although these tumor-infiltrating Tg T cells remained reactive against TRP-2, they did not reduce growth of the primary tumor. These data demonstrate that despite in vivo priming, tumor-infiltrating T cells may fail to reduce tumor burden.