High-Avidity T Cells Are Preferentially Tolerized in the Tumor Microenvironment

One obstacle in eliciting potent antitumor 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 a 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-gamma production and CD107a (Lamp1) mobilization, hallmarks of T-cell tolerization. IFN-gamma expression by TCRhi T cells was critical for upregulation 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 (TADC) 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 show 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. Cancer Res; 73(2); 595-604. (C) 2012 AACR.