Department of Chemical and Biomolecular Engineering, University of Delaware, 150 Academy St., Newark, DE, 19716, USA.
Drug Deliv Transl Res. 2023 Jul;13(7):1955-1966. doi: 10.1007/s13346-023-01319-6. Epub 2023 Mar 14.
Despite recent clinical successes of chimeric antigen receptor T cell therapies in treating liquid cancers, many lingering challenges stand in the way of therapeutic translation to broader types of malignancies. Macrophages have been proposed as alternatives to T cells given macrophages' advantages in promoting tumor infiltration, acquiring diverse antigens, and possessing the ability to continuously stimulate adaptive responses. However, the poor survival of macrophages upon transplantation in addition to transient anti-tumor phenotypical states have been major obstacles standing in the way of macrophage-based cell therapies. Given recent discoveries of nanoparticle strategies in improving macrophage survival and promoting phenotype retention, we herein report the ability to extend the survival and phenotype of macrophage transplants in murine lungs via pre-treatment with nanoparticles of varying degradation rates. Macrophages pre-treated with 100 µg/ml dose of poly(ethylene glycol) diacrylate nanoparticle formulations improve pulmonary macrophage transplant survival over untreated cells beyond 7 days, where degradable nanoparticle formulations result in over a 50% increase in retention of transplanted cell counts relative to untreated cells. Furthermore, pre-treated macrophages more efficiently retain an imposed pro-inflammatory-like polarization state following transplantation out to 7 days compared to macrophages pre-treated with a classical pro-inflammatory stimulus, interferon-gamma, where CD86 costimulatory molecule expression is greater than 150% higher in pre-treated macrophage transplants compared to untreated counterparts. These findings provide an avenue for a major improvement in the lifespan and efficacy of macrophage-based cell therapies and have broader implications to other phagocyte-based cellular therapeutics and administration routes.
尽管嵌合抗原受体 T 细胞疗法在治疗液体癌方面最近取得了临床成功，但在将治疗方法转化为更广泛类型的恶性肿瘤方面，仍存在许多悬而未决的挑战。鉴于巨噬细胞在促进肿瘤浸润、获得多样化抗原以及具有持续刺激适应性反应的能力方面具有优势，因此已被提议替代 T 细胞。然而，巨噬细胞在移植后的存活率低，以及短暂的抗肿瘤表型状态，一直是阻碍基于巨噬细胞的细胞疗法的主要障碍。鉴于最近在纳米粒子策略方面的发现可改善巨噬细胞的存活率并促进表型保留，我们在此报告了通过用不同降解率的纳米粒子预处理来延长鼠肺中巨噬细胞移植的存活和表型的能力。用 100μg/ml 剂量的聚乙二醇二丙烯酸酯纳米粒子制剂预处理的巨噬细胞，与未处理的细胞相比，可将肺巨噬细胞移植的存活时间延长至 7 天以上，其中可降解纳米粒子制剂可使移植细胞数量的保留率相对于未处理的细胞增加 50%以上。此外，与用经典促炎刺激物干扰素-γ预处理的巨噬细胞相比，预处理后的巨噬细胞在移植后 7 天内更有效地保留所施加的促炎样极化状态，其中预处理的巨噬细胞移植中的 CD86 共刺激分子表达比未处理的对照物高 150%以上。这些发现为改善基于巨噬细胞的细胞疗法的寿命和疗效提供了一条途径，并对其他吞噬细胞为基础的细胞治疗和给药途径具有更广泛的意义。
