用于预防肺癌的基于外泌体的癌症疫苗。
Exosome-based cancer vaccine for prevention of lung cancer.
作者信息
Meng Shuhan, Whitt Aaron G, Stamp Bryce F, Eaton John W, Li Chi, Yaddanapudi Kavitha
机构信息
Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.
Experimental Therapeutics Program, Brown Cancer Center, University of Louisville, Louisville, KY, USA.
出版信息
Stem Cell Investig. 2023 Jan 9;10:2. doi: 10.21037/sci-2022-030. eCollection 2023.
BACKGROUND
Our earlier work has shown that a unique stem cell-based vaccine that comprises of murine embryonic stem cells (ESCs) and murine fibroblasts expressing the immunostimulant granulocyte-macrophage colony stimulating factor (GM-CSF) successfully protects mice from the outgrowth of an implantable form of murine lung cancer. The use of live ESCs raises the potential risks of inducing teratomas and autoimmunity. We have attempted to improve the safety and utility of this prophylactic vaccine by employing exosomes derived from murine ESCs engineered to produce GM-CSF (ES-exo/GM-CSF vaccine).
METHODS
We have previously reported that ES-exo/GM-CSF immunization does protect mice from the outgrowth of an implantable form of murine lung cancer. Here, we have investigated the cancer prevention efficacy of ES-exo/GM-CSF vaccine in an experimental metastasis model of murine lung cancer, in which Lewis lung carcinoma (LLC) cells were administered into female C57BL/6 mice (8 weeks of age) through tail vein injection and subsequently LLC tumors were established in lungs.
RESULTS
Our objective is to test the anti-cancer efficacy of ES-exo/GM-CSF vaccine in a mouse model of metastatic lung cancer. Our studies indicate that vaccination of mice with ES-exo/GM-CSF vaccine inhibited the growth of metastatic lung tumors. ES-exo/GM-CSF vactionation reduced lung tumor burden from 1.86% in non-vaccinated, LLC-challenged mice to 0.036% in corresponding vacinnated mice. Importantly, control exosomes without GM-CSF failed to provide protection against metastasized pulmonary tumors. The efficacy of ES-exo/GM-CSF vaccination was associated with a decrease in the frequencies of tumor-infiltrating immunosuppressive immune cells, including T regulatory cells, myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages, as well as an increase in effector cytokine production from intra-tumoral CD8 T cells.
CONCLUSIONS
Overall, our research provides a novel strategy for developing a cell-free prophylactic vaccine against lung tumors.
背景
我们早期的研究表明，一种独特的基于干细胞的疫苗，由小鼠胚胎干细胞（ESC）和表达免疫刺激因子粒细胞-巨噬细胞集落刺激因子（GM-CSF）的小鼠成纤维细胞组成，能够成功保护小鼠免受可植入形式的小鼠肺癌的生长。使用活的ESC会增加诱发畸胎瘤和自身免疫的潜在风险。我们试图通过使用源自经基因工程改造以产生GM-CSF的小鼠ESC的外泌体（ES-exo/GM-CSF疫苗）来提高这种预防性疫苗的安全性和实用性。
方法
我们之前报道过，ES-exo/GM-CSF免疫确实能保护小鼠免受可植入形式的小鼠肺癌的生长。在此，我们研究了ES-exo/GM-CSF疫苗在小鼠肺癌实验性转移模型中的癌症预防效果，在该模型中，通过尾静脉注射将Lewis肺癌（LLC）细胞注入8周龄的雌性C57BL/6小鼠体内，随后在肺部形成LLC肿瘤。
结果
我们的目标是在转移性肺癌小鼠模型中测试ES-exo/GM-CSF疫苗的抗癌效果。我们的研究表明，用ES-exo/GM-CSF疫苗给小鼠接种可抑制转移性肺肿瘤的生长。ES-exo/GM-CSF疫苗接种将肺肿瘤负担从未接种疫苗、受LLC攻击的小鼠中的1.86%降低到相应接种疫苗小鼠中的0.036%。重要的是，不含GM-CSF的对照外泌体未能提供针对转移性肺肿瘤的保护。ES-exo/GM-CSF疫苗接种效果与肿瘤浸润性免疫抑制免疫细胞频率降低有关，这些细胞包括调节性T细胞、髓源性抑制细胞（MDSC）和肿瘤相关巨噬细胞，同时肿瘤内CD8 T细胞产生的效应细胞因子增加。
结论
总体而言，我们的研究为开发一种针对肺肿瘤的无细胞预防性疫苗提供了一种新策略。
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