Mol Cancer Ther. 2023 Apr 3;22(4):499-510. doi: 10.1158/1535-7163.MCT-22-0475.
Eribulin is a microtubule dynamics inhibitor with tumor microenvironment modulation activity such as vascular remodeling activity. Here, we investigated antitumor and immunomodulatory activities of eribulin and its liposomal formulation (eribulin-LF) as monotherapies or in combination with anti-programmed death 1 (PD-1) Ab. The antitumor activity of eribulin or eribulin-LF as monotherapy or in combination with anti-PD-1 Ab was examined in a P-glycoprotein-knockout 4T1 model. Eribulin and eribulin-LF showed stronger antitumor activity in immunocompetent mice compared with immunodeficient mice, indicating that they have immunomodulatory activity that underlies its antitumor activity. Combination therapy of eribulin and eribulin-LF with anti-PD-1 Ab showed antitumor activity, and the combination activity of eribulin-LF with anti-PD-1 Ab was observed at a lower dose and longer interval of administration compared with that using eribulin. To examine the immunomodulatory activity of eribulin and eribulin-LF and its underlying mechanisms, we performed flow cytometry, IHC, and gene expression profiling. IHC and flow cytometry revealed that eribulin-LF increased microvessel density and intratumoral populations of cytotoxic T cells and natural killer cells rather than eribulin. Gene expression profiling demonstrated that eribulin-LF induces IFNγ signaling. Furthermore, IHC also showed that eribulin-LF increased infiltration of CD8-positive cells together with increased CD31-positive cells. Eribulin-LF also increased ICAM-1 expression, which is essential for lymphocyte adhesion to vascular endothelial cells. In conclusion, eribulin showed combination antitumor activity with anti-PD-1 Ab via immunomodulation due to its vascular remodeling activity, and the liposomal formulation showed improved antitumor activity over the standard formulation.
艾立布林是一种微管动力学抑制剂，具有肿瘤微环境调节活性，如血管重塑活性。在这里，我们研究了艾立布林及其脂质体制剂（艾立布林-LF）作为单一疗法或与抗程序性死亡 1（PD-1）Ab 的联合治疗的抗肿瘤和免疫调节活性。在 P-糖蛋白敲除的 4T1 模型中，研究了艾立布林或艾立布林-LF 作为单一疗法或与抗 PD-1 Ab 联合治疗的抗肿瘤活性。与免疫缺陷小鼠相比，艾立布林和艾立布林-LF 在免疫功能正常的小鼠中表现出更强的抗肿瘤活性，表明它们具有免疫调节活性，这是其抗肿瘤活性的基础。艾立布林和艾立布林-LF 与抗 PD-1 Ab 的联合治疗显示出抗肿瘤活性，与使用艾立布林相比，艾立布林-LF 与抗 PD-1 Ab 的联合治疗活性在较低剂量和较长的给药间隔即可观察到。为了研究艾立布林和艾立布林-LF 的免疫调节活性及其潜在机制，我们进行了流式细胞术、免疫组化和基因表达谱分析。免疫组化和流式细胞术显示，艾立布林-LF 增加了微血管密度和肿瘤内细胞毒性 T 细胞和自然杀伤细胞的群体，而不是艾立布林。基因表达谱分析表明，艾立布林-LF 诱导 IFNγ 信号。此外，免疫组化还显示，艾立布林-LF 增加了 CD8 阳性细胞的浸润，同时增加了 CD31 阳性细胞。艾立布林-LF 还增加了 ICAM-1 的表达，这对于淋巴细胞黏附到血管内皮细胞是必需的。总之，艾立布林通过其血管重塑活性与抗 PD-1 Ab 产生联合抗肿瘤活性，而脂质体制剂显示出比标准制剂更好的抗肿瘤活性。
