High-avidity T cells are preferentially tolerized in the tumor microenvironment

One obstacle in eliciting potent anti-tumor immune responses is the induction of tolerance to tumor antigens. TCRlo mice bearing a TCR transgene specific for the melanoma antigen Tyrosinase-related protein-2 (TRP-2, Dct) harbor T cells that maintain tumor antigen responsiveness but lack the ability to control melanoma outgrowth. We used this model to determine whether higher avidity T cells could control tumor growth without becoming tolerized. As part of the current study, we developed a second TRP-2-specific TCR transgenic mouse line (TCRhi) that bears higher avidity T cells and spontaneously developed autoimmune depigmentation. In contrast to TCRlo T cells, which were ignorant of tumor-derived antigen, TCRhi T cells initially delayed subcutaneous B16 melanoma tumor growth. However, persistence in the tumor microenvironment resulted in reduced IFN-γ production and CD107a (Lamp1) mobilization, hallmarks of T cell tolerization. IFN-γ expression by TCRhi T cells was critical for up-regulation of MHC-I on tumor cells and control of tumor growth. Blockade of PD-1 signals prevented T cell tolerization and restored tumor immunity. Depletion of tumor-associated dendritic cells (TADCs) reduced tolerization of TCRhi T cells and enhanced their antitumor activity. In addition, TADCs tolerized TCRhi T cells but not TCRlo T cells in vitro. Our findings demonstrate that T cell avidity is a critical determinant of not only tumor control but also susceptibility to tolerization in the tumor microenvironment. For this reason, care should be exercised when considering T cell avidity in designing cancer immunotherapeutics.