Very low avidity endogenous memory CD8+ T cells control tumor growth (TUM2P.893)

Abstract

Abstract In this study, we describe mice bearing a very low avidity TCR transgene (TCRvlo) specific for a melanoma antigen. Remarkably, a majority of peripheral TCRvlo CD8+ T cells display a phenotype consistent with the expression pattern for endogenous memory (EM) T cells: CD44hi, CXCR3hi, Gr1hi, GITRhi, CD69lo, CD25lo, CD49dlo. This phenotype was not observed among thymic CD8+CD4- TCRvlo T cells. EM-T cells are proposed to arise from naïve T cells in the absence of activation by foreign antigen and are a very rare population of cells which may contribute to primary immune responses, but have not been studied in cancer models. We hypothesize that EM-T cells may provide a unique reservoir of cells that can control tumor growth. Our previous observations indicate that T cells bearing a high avidity TCR with identical antigenic specificity initially control tumor growth but are prone to tumor-induced tolerance. In our preliminary studies, compared to wildtype animals, TCRvlo transgenic mice displayed delayed subcutaneous B16 melanoma growth. In an adoptive transfer setting, TCRvlo T cells also delayed B16 tumor growth compared to untreated animals. Ongoing studies are focused on characterizing the functional responses of the TCRvlo CD8+ T cells to antigen and cytokines as well as determining whether TCRvlo T cells resist tolerization in the tumor microenvironment. Results from these studies may enable us to use EM-T cells as a resource for generating more durable tumor immunity.