Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21205, United States.
Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, United States.
ACS Biomater Sci Eng. 2023 Nov 13;9(11):6438-6450. doi: 10.1021/acsbiomaterials.3c00885. Epub 2023 Oct 5.
Tumor immunotherapy is a promising anticancer strategy; however, tumor cells may employ resistance mechanisms, including downregulation of major histocompatibility complex (MHC) molecules to avoid immune recognition. Here, we investigate reprogramming nanoparticles (NPs) that deliver immunostimulatory genes to enhance immunotherapy and address defective antigen presentation in skin cancer and . We use a modular poly(beta-amino ester) (PBAE)-based NP to deliver DNA encoding 4-1BBL, IL-12, and IFNγ to reprogram human Merkel cell carcinoma (MCC) cells and mouse melanoma tumors to drive adaptive antitumor immune responses. Optimized NP formulations delivering 4-1BBL/IL-12 or 4-1BBL/IL-12/IFNγ DNA successfully transfect MCC and melanoma cells and , respectively, resulting in IFNγ-driven upregulation of MHC class I and II molecules on cancer cells. These NPs reprogram the tumor immune microenvironment (TIME) and elicit strong T-cell-driven immune responses, leading to cancer cell killing and T-cell proliferation and slowing tumor growth and improving survival rates . Based on expected changes to the tumor immune microenvironment, particularly the importance of IFNγ to the immune response and driving both T-cell function and exhaustion, next-generation NPs codelivering IFNγ were designed. These offered mixed benefits, exchanging improved polyfunctionality for increased T-cell exhaustion and demonstrating higher systemic toxicity . Further profiling of the immune response with these NPs provides insight into T-cell exhaustion and polyfunctionality induced by different formulations, providing a greater understanding of this immunotherapeutic strategy.
肿瘤免疫疗法是一种很有前途的抗癌策略；然而，肿瘤细胞可能会采用抵抗机制，包括下调主要组织相容性复合体（MHC）分子以避免免疫识别。在这里，我们研究了重新编程纳米颗粒（NPs），以传递免疫刺激基因来增强免疫疗法，并解决皮肤癌和中的抗原呈递缺陷。我们使用基于模块化聚（β-氨基酯）（PBAE）的 NP 来递送编码 4-1BBL、IL-12 和 IFNγ 的 DNA，以重新编程人类默克尔细胞癌（MCC）细胞和小鼠黑色素瘤肿瘤，以驱动适应性抗肿瘤免疫反应。优化的 NP 制剂递送 4-1BBL/IL-12 或 4-1BBL/IL-12/IFNγ DNA，成功转染 MCC 和黑色素瘤细胞，分别导致 IFNγ 驱动 MHC 类 I 和 II 分子在癌细胞上的上调。这些 NPs 重新编程肿瘤免疫微环境（TIME）并引发强烈的 T 细胞驱动的免疫反应，导致癌细胞杀伤和 T 细胞增殖，并减缓肿瘤生长和提高存活率。基于对肿瘤免疫微环境的预期变化，特别是 IFNγ对免疫反应的重要性以及驱动 T 细胞功能和衰竭，设计了新一代共递送 IFNγ的 NPs。这些提供了混合的好处，用增加的 T 细胞衰竭交换了改善的多功能性，并显示出更高的全身毒性。这些 NPs 的免疫反应进一步分析提供了对不同制剂诱导的 T 细胞衰竭和多功能性的深入了解，从而更深入地了解这种免疫治疗策略。
