Department of Pharmaceutical Sciences, College of Pharmacy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Chemical Engineering, College of Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
Sci Transl Med. 2022 May 4;14(643):eabl3649. doi: 10.1126/scitranslmed.abl3649.
Immunomodulators that remodel the tumor immunosuppressive microenvironment have been combined with anti-programmed death 1 (α-PD1) or anti-programmed death ligand 1 (α-PDL1) immunotherapy but have shown limited success in clinical trials. However, therapeutic strategies to modulate the immunosuppressive microenvironment of lymph nodes have been largely overlooked. Here, we designed an albumin nanoparticle, Nano-PI, containing the immunomodulators PI3Kγ inhibitor (IPI-549) and paclitaxel (PTX). We treated two breast cancer mouse models with Nano-PI in combination with α-PD1, which remodeled the tumor microenvironment in both lymph nodes and tumors. This combination achieved long-term tumor remission in mouse models and eliminated lung metastases. PTX combined with IPI-549 enabled the formation of a stable nanoparticle and enhanced the repolarization of M2 to M1 macrophages. Nano-PI not only enhanced the delivery of both immunomodulators to lymph nodes and tumors but also improved the drug accumulation in the macrophages of these two tissues. Immune cell profiling revealed that the combination of Nano-PI with α-PD1 remodeled the immune microenvironment by polarizing M2 to M1 macrophages, increasing CD4 and CD8 T cells, B cells, and dendritic cells, decreasing regulatory T cells, and preventing T cell exhaustion. Our data suggest that Nano-PI in combination with α-PD1 modulates the immune microenvironment in both lymph nodes and tumors to achieve long-term remission in mice with metastatic breast cancer, and represents a promising candidate for future clinical trials.
免疫调节剂重塑肿瘤免疫抑制微环境已与抗程序性死亡 1（α-PD1）或抗程序性死亡配体 1（α-PDL1）免疫疗法联合使用，但在临床试验中仅取得有限的成功。然而，调节淋巴结免疫抑制微环境的治疗策略在很大程度上被忽视了。在这里，我们设计了一种载有免疫调节剂 PI3Kγ 抑制剂（IPI-549）和紫杉醇（PTX）的白蛋白纳米颗粒，命名为 Nano-PI。我们用 Nano-PI 联合 α-PD1 治疗两种乳腺癌小鼠模型，重塑了淋巴结和肿瘤中的肿瘤微环境。这种联合治疗在小鼠模型中实现了长期的肿瘤缓解，并消除了肺转移。PTX 与 IPI-549 联合使用能够形成稳定的纳米颗粒，并增强 M2 向 M1 巨噬细胞的极化。Nano-PI 不仅增强了两种免疫调节剂向淋巴结和肿瘤的递送，而且提高了这两种组织中巨噬细胞的药物积累。免疫细胞分析表明，Nano-PI 联合 α-PD1 通过将 M2 极化为 M1 巨噬细胞、增加 CD4 和 CD8 T 细胞、B 细胞和树突状细胞、减少调节性 T 细胞和防止 T 细胞耗竭来重塑免疫微环境。我们的数据表明，Nano-PI 联合 α-PD1 调节淋巴结和肿瘤中的免疫微环境，在患有转移性乳腺癌的小鼠中实现长期缓解，是未来临床试验的有前途的候选药物。
