PDF file-439KB, Supplementary Figure S1: Functional avidity of T cell clones 37 vs 24.Supplementary Figure S2: T cells infiltrate the skin of TCRhi mice.Supplementary Figure S3: TCRhi T cells displayed higher functional avidity than TCRlo T cells. Supplementary Figure S4: TCRhi T cells display higher antitumor activity than TCRlo T cells. Supplementary Figure S5: TCRhi not TCRlo T cells infiltrating subcutaneous B16 tumors TCR , TCR become tolerized. Supplementary Figure S6: MHC-I expression on tumor cells was up-regulated after transfer of TCR Tg T cells. Supplementary Figure S7: PD-1 blockade prevent TcRhi tolerization. Supplementary Figure S8: TADCs isolated from B16 tumor express CD11c+/B220+/BST2 (CD317)+. Supplementary Figure S9: Foxo3-/- B16 TADCs do not tolerize TCRhi T cells in vitro. Supplementary Figure S10: Depletion of TADCs with anti-CD317 Ab in subcutaneous B16 tumor. Supplementary Figure S11: Administration of anti-CD317 alone does not alter B16 tumor growth.
ARTICLE ABSTRACT
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-γ production and CD107a (Lamp1) mobilization, hallmarks of T-cell tolerization. IFN-γ 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. ©2012 AACR.
