Adoptive transfer of cytotoxic T lymphocytes (CTLs) has been used as an immunotherapy in melanoma. However, the tumor homing and therapeutic efficacy of transferred CTLs against melanoma remain unsatisfactory. Interleukin-4 receptor (IL-4R) is commonly up-regulated in tumors including melanoma. Here, we studied whether IL-4R-targeted CTLs exhibit enhanced tumor homing and therapeutic efficacy against melanoma. CTLs isolated from mice bearing melanomas were non-genetically engineered with IL4RPep-1, an IL-4R-binding peptide, using a membrane anchor composed of dioleylphosphatidylethanolamine. Compared to control CTLs, IL-4R-targeted CTLs showed higher binding to melanoma cells and in vivo tumor homing. They also exerted a more rapid and robust effector response, including increased cytokine secretion and cytotoxicity against melanoma cells and enhanced reprogramming of M2-type macrophages to M1-type macrophages. Moreover, IL-4R-targeted CTLs efficiently inhibited melanoma growth and reversed the immunosuppressive tumor microenvironment. These results suggest that non-genetically engineered CTLs targeting IL-4R have potential as an adoptive T cell therapy against melanoma.

细胞毒性T淋巴细胞（CTL）的过继转移已被用作黑色素瘤的免疫疗法。然而，转移的CTL针对黑素瘤的肿瘤归巢和治疗功效仍然不能令人满意。白细胞介素4受体（IL-4R）通常在包括黑素瘤在内的肿瘤中被上调。在这里，我们研究了靶向IL-4R的CTL是否表现出增强的肿瘤归巢性和针对黑色素瘤的治疗功效。使用由二油基磷脂酰乙醇胺组成的膜锚，用IL4RPep-1（一种IL-4R结合肽）对从黑素瘤小鼠中分离的CTL进行非基因工程改造。与对照CTL相比，靶向IL-4R的CTL对黑色素瘤细胞和体内的结合更高肿瘤归巢。他们还发挥了更快，更强的效应器反应，包括增加的细胞因子分泌和针对黑素瘤细胞的细胞毒性，以及增强了将M2型巨噬细胞重编程为M1型巨噬细胞的能力。而且，靶向IL-4R的CTL有效抑制黑素瘤的生长并逆转免疫抑制肿瘤的微环境。这些结果表明，靶向IL-4R的非基因工程CTL具有潜在的抗黑素瘤T细胞过继治疗的作用。