Biomaterial-Mediated Genetic Reprogramming of Merkel Cell Carcinoma and Melanoma Leads to Targeted Cancer Cell Killing In Vitro and In Vivo.
Biomaterial-Mediated Genetic Reprogramming of Merkel Cell Carcinoma and Melanoma Leads to Targeted Cancer Cell Killing In Vitro and In Vivo.
复制标题
DOI：
10.1021/acsbiomaterials.3c00885
复制
发表时间：
2023-11-13
影响因子：
5.8
通讯作者：
Tzeng, Stephany Y.
中科院分区：
文献类型：
--
作者：
Luly, Kathryn M.;Green, Jordan J.;Sunshine, Joel C.;Tzeng, Stephany Y.
肿瘤免疫疗法是一种有前景的抗癌策略；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，我们研究了重编程纳米颗粒（NP），它可以传递免疫刺激基因，以增强免疫治疗并解决体外和体内皮肤癌中抗原呈递缺陷的问题。我们使用基于模块化聚（β-氨基酯）（PBAE）的 NP 来传递编码 4-1BBL、IL-12 和 IFNγ 的 DNA，以在体外重新编程人类默克尔细胞癌（MCC）细胞和在体内重新编程小鼠黑色素瘤肿瘤，以驱动适应性抗肿瘤免疫反应。优化的 NP 制剂可递送 4-1BBL/IL-12 或 4-1BBL/IL-12/IFNγ DNA，分别在体外和体内成功转染 MCC 和黑色素瘤细胞，导致癌细胞上 IFNγ 驱动的 MHC I 类和 II 类分子上调。这些纳米粒子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，导致体外癌细胞杀伤和T细胞增殖，并减缓肿瘤生长并提高体内存活率。基于肿瘤免疫微环境的预期变化，特别是 IFNγ 对免疫反应以及驱动 T 细胞功能和耗竭的重要性，设计了共同传递 IFNγ 的下一代 NP。这些带来了混合的好处，用改进的多功能性换来了增加的 T 细胞耗竭，并在体内表现出更高的全身毒性。进一步分析这些纳米颗粒的免疫反应可以深入了解不同制剂诱导的 T 细胞耗竭和多功能性，从而更好地理解这种免疫治疗策略。
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 in vitro and in vivo. 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 in vitro and mouse melanoma tumors in vivo 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 in vitro and in vivo, 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 in vitro and slowing tumor growth and improving survival rates in vivo. 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 in vivo. 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.
登录
查看更多内容
影响因子：
11.5
作者：
Bhatia, Shailender;Longino, Natalie V.;Miller, Natalie J.;Kulikauskas, Rima;Iyer, Jayasri G.;Ibrani, Dafina;Blom, Astrid;Byrd, David R.;Parvathaneni, Upendra;Twitty, Christopher G.;Campbell, Jean S.;Le, Mai H.;Gargosky, Sharron;Pierce, Robert H.;Heller, Richard;Daud, Adil I.;Nghiem, Paul
通讯作者：
Nghiem, Paul
DOI：
10.1073/pnas.1916039117
发表时间：
2020-02-25
影响因子：
11.1
作者：
Tzeng, Stephany Y.;Patel, Kisha K.;Green, Jordan J.
通讯作者：
Green, Jordan J.
影响因子：
10.8
作者：
Liu, Jin-Qing;Zhang, Chengxiang;Zhang, Xinfu;Yan, Jingyue;Zeng, Chunxi;Talebian, Fatemeh;Lynch, Kimberly;Zhao, Weiyu;Hou, Xucheng;Du, Shi;Kang, Diana D.;Deng, Binbin;McComb, David W.;Bai, Xue-Feng;Dong, Yizhou
通讯作者：
Dong, Yizhou
影响因子：
64.8
作者：
Mellman, Ira;Coukos, George;Dranoff, Glenn
通讯作者：
Dranoff, Glenn
聚合物结构和降解机制的微妙变化使纳米颗粒能够高效地将 siRNA 和 DNA 运送到人类脑癌患者体内。
影响因子：
10
作者：
Tzeng, Stephany Y.;Green, Jordan J.
通讯作者：
Green, Jordan J.