Authors' Affiliations: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University;
Authors' Affiliations: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University; Immunotherapy Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Korea;
Cancer Res. 2014 Jul 1;74(13):3556-66. doi: 10.1158/0008-5472.CAN-13-3225. Epub 2014 Apr 25.
Identifying immune escape mechanisms used by tumors may define strategies to sensitize them to immunotherapies to which they are otherwise resistant. In this study, we show that the antiapoptotic gene API5 acts as an immune escape gene in tumors by rendering them resistant to apoptosis triggered by tumor antigen-specific T cells. Its RNAi-mediated silencing in tumor cells expressing high levels of API5 restored antigen-specific immune sensitivity. Conversely, introducing API5 into API5(low) cells conferred immune resistance. Mechanistic investigations revealed that API5 mediated resistance by upregulating FGF2 signaling through a FGFR1/PKCδ/ERK effector pathway that triggered degradation of the proapoptotic molecule BIM. Blockade of FGF2, PKCδ, or ERK phenocopied the effect of API5 silencing in tumor cells expressing high levels of API5 to either murine or human antigen-specific T cells. Our results identify a novel mechanism of immune escape that can be inhibited to potentiate the efficacy of targeted active immunotherapies.
识别肿瘤使用的免疫逃逸机制可能会定义使它们对免疫疗法敏感的策略，否则它们会对此类疗法产生抗性。在这项研究中，我们表明凋亡抑制基因 API5 通过使肿瘤细胞对肿瘤抗原特异性 T 细胞触发的细胞凋亡产生抗性，从而充当肿瘤中的免疫逃逸基因。在高表达 API5 的肿瘤细胞中，其 RNAi 介导的沉默恢复了抗原特异性免疫敏感性。相反，将 API5 引入 API5(low) 细胞中则赋予了免疫抗性。机制研究表明，API5 通过上调 FGF2 信号传导来介导耐药性，该信号传导通过 FGFR1/PKCδ/ERK 效应途径触发促凋亡分子 BIM 的降解。在高表达 API5 的肿瘤细胞中，阻断 FGF2、PKCδ 或 ERK 可模拟 API5 沉默对鼠或人抗原特异性 T 细胞的作用。我们的研究结果确定了一种新的免疫逃逸机制，该机制可被抑制以增强靶向主动免疫疗法的疗效。
