Bulliard Yannick, Jolicoeur Rose, Zhang Jimin, Dranoff Glenn, Wilson Nicholas S, Brogdon Jennifer L
Department of Oncology, Novartis Institute for Biomedical Research, Cambridge, MA, USA.
Department of Laboratory Animal Services, Novartis Institute for Biomedical Research, Cambridge, MA, USA.
Immunol Cell Biol. 2014 Jul;92(6):475-80. doi: 10.1038/icb.2014.26. Epub 2014 Apr 15.
Antibodies targeting checkpoint inhibitors or co-stimulatory receptors on T cells have shown significant antitumor efficacy in preclinical and clinical studies. In mouse tumor models, engagement of activating Fcγ receptor (FcγR)-expressing immune cells was recently shown to be required for the tumoricidal activity of antibodies recognizing the tumor necrosis factor superfamily receptor (TNFR) GITR (CD357) and CTLA-4 (CD152). In particular, activating FcγRs facilitated the selective elimination of intratumoral T-cell populations. However, it remains unclear whether FcγRs contribute to the antitumor efficacy of other immunomodulatory antibodies. Here, we explored the mechanism of antitumor activity mediated by an agonistic antibody (clone OX86) to the co-stimulatory TNFR OX40 (CD134). OX40 was highly expressed by intratumoral T cells, particularly those of the FoxP3(+) regulatory T-cell (Treg) lineage. OX86 administration resulted in the depletion of intratumoral regulatory T cells in an activating FcγR-dependent manner, which correlated with tumor regression. Together with previous data from our group and others, these findings support a mechanism whereby antibodies targeting antigens highly expressed by intratumoral T cells can mediate their elimination by FcγR-expressing immune cells, and facilitate subsequent antitumor immunity.
靶向T细胞上检查点抑制剂或共刺激受体的抗体在临床前和临床研究中已显示出显著的抗肿瘤疗效。在小鼠肿瘤模型中，最近发现识别肿瘤坏死因子超家族受体（TNFR）GITR（CD357）和CTLA-4（CD152）的抗体的杀肿瘤活性需要表达激活型Fcγ受体（FcγR）的免疫细胞的参与。特别是，激活型FcγR促进了肿瘤内T细胞群体的选择性清除。然而，FcγR是否有助于其他免疫调节抗体的抗肿瘤疗效仍不清楚。在这里，我们探讨了一种针对共刺激TNFR OX40（CD134）的激动性抗体（克隆OX86）介导的抗肿瘤活性机制。OX40在肿瘤内T细胞中高度表达，尤其是FoxP3（+）调节性T细胞（Treg）谱系的细胞。给予OX86导致肿瘤内调节性T细胞以依赖激活型FcγR的方式耗竭，这与肿瘤消退相关。结合我们小组和其他小组以前的数据，这些发现支持了一种机制，即靶向肿瘤内T细胞高度表达的抗原的抗体可以通过表达FcγR的免疫细胞介导其清除，并促进随后的抗肿瘤免疫。
