Effect of self antigen specific CD4+ T cell precursor frequency on the anti-tumor immune response: Implications for adoptive T cell therapy (P2040)

Abstract

Abstract Current approaches to cancer immunotherapy aim to enhance the natural T cell response against tumors; however, these treatments may fall short due to the negative selection of tumor antigen specific T cells. To determine how frequency of CD4+ T cells may shape an anti-tumor response we have developed a model in which precursor number can be manipulated in mice bearing implantable melanoma through the adoptive transfer of tumor specific T cells. We have previously shown that lower frequencies of CD8+ T cells specific for melanoma antigen gp100 generate the most productive response due to intraclonal competition at higher concentrations. Unlike CD8+ T cells, the adoptive transfer of greater quantities of CD4+ T cells specific for melanoma antigen TRP-1 results in better tumor regression. The activation and expansion of CD4+ T cells at high precursor frequencies is diminished compared to lower frequencies, which indicates the occurrence of intraclonal competition. We believe the observed differences in tumor eradication are due to increased infiltration of TRP-1 CD4+ T cells into the tumor when present at high precursor frequencies with lower precursor frequencies favoring the preferential accumulation of TRP-1 specific Foxp3+ regulatory T cells both in the tumor and periphery. Further understanding of how antigen specific regulatory T cells develop and shape the effector response may have implications for the use and improvement of CD4+ T cells in adoptive cell therapy.