Inducing Tumor Suppressive Microenvironments through Genome Edited CD47−/− Syngeneic Cell Vaccination
Inducing Tumor Suppressive Microenvironments through Genome Edited CD47−/− Syngeneic Cell Vaccination
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DOI：
10.1038/s41598-019-56370-6
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发表时间：
2019-12
影响因子：
4.6
通讯作者：
Subhadra Jayaraman Rukmini;Huanjing Bi;Puloma Sen;B. Everhart;Sha Jin;K. Ye
中科院分区：
文献类型：
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作者：
Subhadra Jayaraman Rukmini;Huanjing Bi;Puloma Sen;B. Everhart;Sha Jin;K. Ye
肿瘤可以通过过度表达 CD47 和其他检查点封锁来逃避免疫系统。 CD47 在体内所有细胞中普遍表达，由于其全身毒性，给 CD47 阻断治疗带来了障碍。我们进行了一项研究，以确定在接种基因组编辑的 CD47−/− 同基因肿瘤细胞后肿瘤微环境如何变化。我们发现灭活的 CD47 耗尽的小鼠黑色素瘤细胞可以保护小鼠免受黑色素瘤的侵害。我们的动物研究表明，33% 的接种疫苗的小鼠保持无肿瘤状态，100% 的小鼠生长速度降低了 5 倍。疫苗免疫调节作用的表征揭示了疫苗接种后具有高度抗肿瘤性和均质的微环境。我们一致观察到，在对疫苗没有反应的肿瘤中，自然杀伤细胞减少，调节性 T 细胞、M2 型巨噬细胞升高，并且这些细胞中 PD-L1 表达高。这些观察结果表明，接种疫苗后肿瘤微环境对肿瘤生长的抑制作用更强，这表明实体瘤有可能成为一种新的免疫疗法。
Tumors can escape from the immune system by overexpressing CD47 and other checkpoint blockades. CD47 is expressed ubiquitously by all cells in the body, posing an obstacle for CD47 blocking treatments due to their systemic toxicity. We performed a study to determine how the tumor microenvironment changes after vaccination with genome edited CD47−/−syngeneic tumor cells. We discovered that inactivated CD47-depleted mouse melanoma cells can protect mice from melanoma. Our animal study indicated that 33% of vaccinated mice remained tumor-free, and 100% of mice had 5-fold reduced growth rates. The characterization of immunomodulatory effects of the vaccine revealed a highly anti-tumorigenic and homogenous microenvironment after vaccination. We observed consistently that in the tumors that failed to respond to vaccines, there were reduced natural killer cells, elevated regulatory T cells, M2-type macrophages, and high PD-L1 expression in these cells. These observations suggested that the tumor microenvironments became more suppressive to tumor growth after vaccination, suggesting a potential new immunotherapy for solid tumors.