Aptamer-Mediated Blockade of IL4Rα Triggers Apoptosis of MDSCs and Limits Tumor Progression
Aptamer-Mediated Blockade of IL4Rα Triggers Apoptosis of MDSCs and Limits Tumor Progression
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DOI：
10.1158/0008-5472.can-11-2772
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发表时间：
2012-03-15
期刊：
影响因子：
11.2
通讯作者：
Serafini, Paolo
中科院分区：
文献类型：
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作者：
Roth, Felix;De La Fuente, Adriana C.;Serafini, Paolo
除了通过增强血管生成和侵袭来促进肿瘤进展和转移外，髓源性抑制细胞 (MDSC) 和肿瘤相关巨噬细胞 (TAM) 还会抑制抗肿瘤 T 细胞功能并限制免疫治疗干预的功效。尽管这些白细胞群很重要，但尚未开发出一种简单的特异性去除白细胞群的方法。在这项研究中，我们生成了一种 RNA 适体，可以阻断对 MDSC 抑制功能至关重要的小鼠或人类 IL-4 受体-α（IL4R α 或 CD 124）。在荷瘤小鼠中，这种抗 IL4R α 适体优先靶向 MDSC 和 TAM，并出乎意料地促进了它们的消除，这种效应与肿瘤浸润 T 细胞数量增加和肿瘤生长减少有关。 MDSC 中适体触发细胞凋亡的机制研究证实了 IL4R α-STAT6 通路激活在 MDSC 存活中的重要性。我们的研究结果定义了一种在体内消除 MDSC 和 TAM 的简单策略，并强化了 IL4R α 信号传导对于 MDSC 存活至关重要的概念。更广泛地说，这些发现表明基于 IL4R α 信号传导阻断的治疗策略可以阻止癌症中由 MDSC 和 TAM 介导的肿瘤免疫逃逸的重要细胞机制。癌症注册； 72(6)； 1373-83。 (C) 2012 AACR
In addition to promoting tumor progression and metastasis by enhancing angiogenesis and invasion, myeloid-derived suppressor cells (MDSC) and tumor-associated macrophage (TAM) also inhibit antitumor T-cell functions and limit the efficacy of immunotherapeutic interventions. Despite the importance of these leukocyte populations, a simple method for their specific depletion has not been developed. In this study, we generated an RNA aptamer that blocks the murine or human IL-4 receptor-alpha (IL4R alpha or CD 124) that is critical for MDSC suppression function. In tumor-bearing mice, this anti-IL4R alpha aptamer preferentially targeted MDSCs and TAM and unexpectedly promoted their elimination, an effect that was associated with an increased number of tumor-infiltrating T cells and a reduction in tumor growth. Mechanistic investigations of aptamer-triggered apoptosis in MDSCs confirmed the importance of IL4R alpha-STAT6 pathway activation in MDSC survival. Our findings define a straightforward strategy to deplete MDSCs and TAMs in vivo, and they strengthen the concept that IL4R alpha signaling is pivotal for MDSC survival. More broadly, these findings suggest therapeutic strategies based on IL4R alpha signaling blockades to arrest an important cellular mechanism of tumoral immune escape mediated by MDSCs and TAM in cancer. Cancer Reg; 72(6); 1373-83. (C) 2012 AACR