Cellular cross-talk between tumors and M2-polarized tumor-associated macrophages (TAM) favors tumor progression. Upregulation of IL4 receptor (IL4R) is observed in diverse tumors and TAMs. We tested whether an IL4R-targeted proapoptotic peptide could inhibit tumor progression. The IL4R-binding peptide (IL4RPep-1) preferentially bound to IL4R-expressing tumor cells and M2-polarized macrophages both in vitro and in 4T1 breast tumors in vivo. To selectively kill IL4R-expressing cells, we designed an IL4R-targeted proapoptotic peptide, IL4RPep-1-K, by adding the proapoptotic peptide (KLAKLAK)2 to the end of IL4RPep-1. IL4RPep-1-K exerted selective cytotoxicity against diverse IL4R-expressing tumor cells and M2-polarized macrophages. Systemic administration of IL4RPep-1-K inhibited tumor growth and metastasis in 4T1 breast tumor-bearing mice. Interestingly, IL4RPep-1-K treatment increased the number of activated cytotoxic CD8+ T cells while reducing the numbers of immunosuppressive regulatory T cells and M2-polarized TAMs. No significant systemic side effects were observed. These results suggest that IL4R-targeted proapoptotic peptide has potential for treating diverse IL4R-expressing cancers. Mol Cancer Ther; 16(12); 2803–16. ©2017 AACR.

中文翻译：

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白细胞介素4受体靶向促凋亡肽通过增强抗肿瘤免疫阻断肿瘤生长和转移

肿瘤和 M2 极化的肿瘤相关巨噬细胞 (TAM) 之间的细胞串扰有利于肿瘤进展。在多种肿瘤和 TAM 中观察到 IL4 受体 (IL4R) 的上调。我们测试了靶向 IL4R 的促凋亡肽是否可以抑制肿瘤进展。IL4R 结合肽 (IL4RPep-1) 在体外和体内 4T1 乳腺肿瘤中优先结合表达 IL4R 的肿瘤细胞和 M2 极化的巨噬细胞。为了选择性杀死表达 IL4R 的细胞，我们通过将促凋亡肽 (KLAKLAK)2 添加到 IL4RPep-1 的末端，设计了 IL4R 靶向促凋亡肽 IL4RPep-1-K。IL4RPep-1-K 对多种表达 IL4R 的肿瘤细胞和 M2 极化巨噬细胞发挥选择性细胞毒性。IL4RPep-1-K 的全身给药抑制了 4T1 乳腺癌荷瘤小鼠的肿瘤生长和转移。有趣的是，IL4RPep-1-K 处理增加了活化的细胞毒性 CD8+ T 细胞的数量，同时减少了免疫抑制性调节性 T 细胞和 M2 极化 TAM 的数量。没有观察到显着的全身副作用。这些结果表明靶向 IL4R 的促凋亡肽具有治疗多种表达 IL4R 的癌症的潜力。摩尔癌症治疗; 16(12); 2803-16。©2017 AACR。