Interleukin 4 receptor-targeted pro-apoptotic peptide blocks tumor growth and metastasis by enhancing anti-tumor immunity

Cellular crosstalk between tumors and M2-polarized tumor-associated macrophages (TAMs) favors tumor progression. Upregulation of interleukin 4 receptor (IL4R) is observed in diverse tumors and TAMs. We tested whether an IL4R-targeted pro-apoptotic 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 pro-apoptotic peptide, IL4RPep-1-K, by adding the pro-apoptotic 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 pro-apoptotic peptide has potential for treating diverse IL4R-expressing cancers.

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