The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
Mol Ther. 2019 May 8;27(5):922-932. doi: 10.1016/j.ymthe.2019.02.011. Epub 2019 Feb 16.
IL-15 is a proinflammatory cytokine that plays an essential role in the development and activation of natural killer (NK) cells. Adipose tissue acts as an endocrine organ that secretes cytokines and is an important reservoir for lymphocytes. We hypothesized that activation of the IL-15 signaling in adipose tissue will activate and expand the NK cell population and control tumor growth. We recently developed an adipocyte-targeting recombinant adeno-associated viral (rAAV) vector with minimal off-target transgene expression in the liver. Here, we used this rAAV system to deliver an IL-15/IL-15Rα complex to the abdominal fat by intraperitoneal (i.p.) injection. Adipose IL-15/IL-15Rα complex gene transfer led to the expansion of NK cells in the adipose tissue and spleen in normal mice without notable side effects. The i.p. injection of rAAV-IL-15/IL-15Rα complex significantly suppressed the growth of Lewis lung carcinoma implanted subcutaneously and exerted a significant survival advantage in a B16-F10 melanoma metastasis model. The antitumor effects were associated with the expansion of the NK cells in the blood, spleen, abdominal fat, and tumor, as well as the enhancement of NK cell maturity. Our proof-of-concept preclinical studies demonstrate the safety and efficacy of the adipocyte-specific IL-15/IL-15Rα complex vector as a novel cancer immune gene therapy.
白细胞介素-15（IL-15）是一种促炎细胞因子，在自然杀伤（NK）细胞的发育和激活中发挥着重要作用。脂肪组织作为一种内分泌器官，分泌细胞因子，是淋巴细胞的重要储存库。我们假设脂肪组织中 IL-15 信号的激活将激活和扩增 NK 细胞群并控制肿瘤生长。我们最近开发了一种脂肪细胞靶向重组腺相关病毒（rAAV）载体，在肝脏中的非靶标转基因表达最小。在这里，我们通过腹腔内（i.p.）注射使用该 rAAV 系统将 IL-15/IL-15Rα 复合物递送至腹部脂肪。脂肪组织中 IL-15/IL-15Rα 复合物基因转移导致正常小鼠脂肪组织和脾脏中 NK 细胞的扩增，没有明显的副作用。rAAV-IL-15/IL-15Rα 复合物的 i.p. 注射显著抑制了皮下植入的 Lewis 肺癌的生长，并在 B16-F10 黑色素瘤转移模型中发挥了显著的生存优势。抗肿瘤作用与血液、脾脏、腹部脂肪和肿瘤中 NK 细胞的扩增以及 NK 细胞成熟度的增强有关。我们的概念验证临床前研究证明了脂肪细胞特异性 IL-15/IL-15Rα 复合物载体作为一种新型癌症免疫基因治疗的安全性和有效性。
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