脂肪细胞：IL-15 /IL-15Rα癌症基因治疗的新靶标。,Molecular Therapy

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脂肪细胞：IL-15 /IL-15Rα癌症基因治疗的新靶标。
Molecular Therapy ( IF 12.1 ) Pub Date : 2019-02-16 , DOI: 10.1016/j.ymthe.2019.02.011
Run Xiao ₁ , Anthony G Mansour ₂ , Wei Huang ₁ , Logan A Chrislip ₁ , Ryan K Wilkins ₁ , Nicholas J Queen ₁ , Youssef Youssef ₃ , Hsiaoyin C Mao ₂ , Michael A Caligiuri ₄ , Lei Cao ₁

Affiliation

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起着至关重要的作用。脂肪组织起分泌细胞因子的内分泌器官的作用，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展NK细胞群体并控制肿瘤的生长。我们最近开发了一种靶向脂肪细胞的重组腺相关病毒（rAAV）载体，在肝脏中具有最小的脱靶转基因表达。在这里，我们使用该rAAV系统通过腹膜内（ip）注射将IL-15 /IL-15Rα复合物递送至腹部脂肪。脂肪IL-15 /IL-15Rα复合基因的转移导致正常小鼠中脂肪组织和脾脏中NK细胞的扩增，而没有明显的副作用。ip 注射rAAV-IL-15 /IL-15Rα复合物可显着抑制皮下植入的Lewis肺癌的生长，并在B16-F10黑色素瘤转移模型中发挥显着的生存优势。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细胞成熟度的提高有关。我们的概念验证的临床前研究证明了脂肪细胞特异性IL-15 /IL-15Rα复合载体作为一种新型的癌症免疫基因疗法的安全性和有效性。以及增强NK细胞的成熟度。我们的概念验证的临床前研究证明了脂肪细胞特异性IL-15 /IL-15Rα复合载体作为一种新型的癌症免疫基因疗法的安全性和有效性。以及增强NK细胞的成熟度。我们的概念验证的临床前研究证明了脂肪细胞特异性IL-15 /IL-15Rα复合载体作为一种新型的癌症免疫基因疗法的安全性和有效性。

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Adipocytes: A Novel Target for IL-15/IL-15Rα Cancer Gene Therapy.

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.

更新日期：2019-02-16

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