title: High-avidity T cells are preferentially tolerized in the tumor microenvironment.
abstract: 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.
authors.affiliation: Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, NCI, Frederick, MD 21702, USA.
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Zhu
authors.forename: Vinod
authors.initials: V
authors.lastname: Singh
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Watkins
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Shoe
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Hurwitz
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D007108:Immune Tolerance; D019746:Intramolecular Oxidoreductases / Q000276:immunology*; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*; D059016:Tumor Microenvironment
chemical_list: D000951:Antigens, Neoplasm; D011948:Receptors, Antigen, T-Cell; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase