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Cancer Res. 2013 Jan 15;73(2):595-604. doi: 10.1158/0008-5472.CAN-12-1123. Epub 2012 Nov 30.

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

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  • 1Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, NCI, Frederick, MD 21702, USA.


One obstacle in eliciting potent antitumor immune responses is the induction of tolerance to tumor antigens. TCR(lo) 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 (TCR(hi)) that bears higher avidity T cells and spontaneously developed autoimmune depigmentation. In contrast to TCR(lo) T cells, which were ignorant of tumor-derived antigen, TCR(hi) 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 TCR(hi) 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 TCR(hi) T cells and enhanced their antitumor activity. In addition, TADCs tolerized TCR(hi) T cells but not TCR(lo) 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.

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