Department of Biochemistry and Cell Biology, Kyungpook National University, Daegu, Korea.
BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Korea.
Mol Cancer Ther. 2017 Dec;16(12):2803-2816. doi: 10.1158/1535-7163.MCT-17-0339. Epub 2017 Sep 6.
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 and in 4T1 breast tumors To selectively kill IL4R-expressing cells, we designed an IL4R-targeted proapoptotic peptide, IL4RPep-1-K, by adding the proapoptotic peptide (KLAKLAK) 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. .
肿瘤细胞与 M2 极化的肿瘤相关巨噬细胞（TAM）之间的细胞通讯有利于肿瘤进展。在多种肿瘤和 TAMs 中观察到白细胞介素 4 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）优先结合表达 IL4R 的肿瘤细胞和 M2 极化的巨噬细胞 ，并在 4T1 乳腺癌肿瘤中 为了选择性地杀死表达 IL4R 的细胞，我们通过在 IL4RPep-1 的末端添加促凋亡肽（KLAKLAK）来设计靶向 IL4R 的促凋亡肽 IL4RPep-1-K。IL4RPep-1-K 对多种表达 IL4R 的肿瘤细胞和 M2 极化的巨噬细胞具有选择性细胞毒性。IL4RPep-1-K 的系统给药抑制了 4T1 乳腺癌荷瘤小鼠的肿瘤生长和转移。有趣的是，IL4RPep-1-K 治疗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 T 细胞和 M2 极化的 TAM 的数量。未观察到明显的全身副作用。这些结果表明，靶向 IL4R 的促凋亡肽有可能治疗多种表达 IL4R 的癌症。
