Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, NCI, Frederick, MD 21702, USA.
Cancer Res. 2013 Jan 15;73(2):595-604. doi: 10.1158/0008-5472.CAN-12-1123. Epub 2012 Nov 30.
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.
激发有效抗肿瘤免疫反应的一个障碍是诱导对肿瘤抗原的耐受。表达黑色素瘤抗原酪氨酸相关蛋白-2（TRP-2，Dct）特异性 TCR 的 TCR(lo) 小鼠携带能够维持肿瘤抗原反应性但缺乏控制黑色素瘤生长能力的 T 细胞。我们使用该模型来确定更高亲和力的 T 细胞是否可以在不被耐受的情况下控制肿瘤生长。作为当前研究的一部分，我们开发了第二个 TRP-2 特异性 TCR 转基因小鼠系（TCR(hi)），该小鼠系携带更高亲和力的 T 细胞并自发发生自身免疫性脱色素。与对肿瘤衍生抗原无知的 TCR(lo) T 细胞相反，TCR(hi) T 细胞最初延迟了皮下 B16 黑色素瘤肿瘤的生长。然而，在肿瘤微环境中的持续存在导致 IFN-γ 产生和 CD107a（Lamp1）动员减少，这是 T 细胞耐受的标志。TCR(hi) T 细胞的 IFN-γ 表达对于上调肿瘤细胞上的 MHC-I 和控制肿瘤生长至关重要。阻断 PD-1 信号可防止 T 细胞耐受并恢复肿瘤免疫。耗尽肿瘤相关树突状细胞（TADC）可减少 TCR(hi) T 细胞的耐受并增强其抗肿瘤活性。此外，TADCs 耐受 TCR(hi) T 细胞但不耐受 TCR(lo) T 细胞体外。我们的研究结果表明，T 细胞亲和力不仅是肿瘤控制的关键决定因素，也是肿瘤微环境中易感性的关键决定因素。因此，在设计癌症免疫疗法时，应谨慎考虑 T 细胞亲和力。
