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...

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Bibliographic Details
Published in:Molecular therapy 2019-05, Vol.27 (5), p.922-932
Main Authors: Xiao, Run, Mansour, Anthony G., Huang, Wei, Chrislip, Logan A., Wilkins, Ryan K., Queen, Nicholas J., Youssef, Youssef, Mao, Hsiaoyin C., Caligiuri, Michael A., Cao, Lei
Format: Article
Language:English
Subjects:
Abdominal Fat - drug effects
Abdominal Fat - immunology
adipocyte
Adipocytes
Adipocytes - drug effects
Adipocytes - immunology
Adipocytes - metabolism
Adipose tissue
Animals
Antitumor activity
Blood tests
cancer
Cancer therapies
Carcinoma, Lewis Lung - genetics
Carcinoma, Lewis Lung - immunology
Carcinoma, Lewis Lung - therapy
Cell activation
Cell Proliferation - genetics
Conflicts of interest
Cytokines
Cytotoxicity
Dependovirus
Flow cytometry
Gene Expression Regulation, Neoplastic - drug effects
Gene therapy
Genetic Therapy
Genetic Vectors - pharmacology
Humans
IL-15/IL-15Rα
immune therapy
Immunotherapy
Inflammation
Injection
Interleukin 15
Interleukin-15 - genetics
Interleukin-15 - pharmacology
Interleukin-15 Receptor alpha Subunit - genetics
Killer Cells, Natural - drug effects
Killer Cells, Natural - immunology
Liver
Liver - drug effects
Liver - immunology
Liver - pathology
Lung carcinoma
Lymphocytes
Melanoma
Melanoma, Experimental - genetics
Melanoma, Experimental - therapy
Metastases
Mice
Natural killer cells
Neoplasm Metastasis
Neoplasms - genetics
Neoplasms - immunology
Neoplasms - pathology
Neoplasms - therapy
NK cell
Original
rAAV
Signal Transduction - genetics
Software
Spleen
visceral fat
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Summary: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. [Display omitted] Cao and colleagues have designed a rAAV vector that selectively overexpresses IL-15/IL-15Rα in the adipocytes. A single intraperitoneal injection of this vector exhibits sustained levels of IL-15/IL-15Rα in the circulation with a strong safety profile and significant anti-tumor activity, supporting the pursuit of this mode of immunotherapy.
ISSN:1525-0016
1525-0024
DOI:10.1016/j.ymthe.2019.02.011