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Tumor growth and metastasis suppression by Glipr1 gene-modified macrophages in a metastatic prostate cancer model

Gene Therapy volume 18, pages 969–978 (2011)Cite this article

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Abstract

We previously identified the mouse and human Glipr1 and GLIPR1/RTVP-1 genes, respectively, as direct p53 targets with proapoptotic activities in various cancer cell lines, including prostate cancer (PCa). Intratumoral injection of an adenoviral vector capable of efficient transduction and expression of Glipr1 (AdGlipr1) yielded promising therapeutic results in an orthotopic, metastatic mouse model of PCa. AdGlipr1-transduced macrophages (Mφ/Glipr1) generated greater surface expression of CD40, CD80 and major histocompatibility complex class II molecules and greater production of interleukin 12 (IL-12) and IL-6 in vitro than control macrophages did. Mechanistic analysis indicated that increased production of IL-12 in Mφ/Glipr1 depends on activation of the p38 signaling cascade. Mφ/Glipr1 injected into orthotopic 178-2BMA tumors in vivo resulted in significantly suppressed prostate tumor growth and spontaneous lung metastases and longer survival relative to those observed in control-treated mice. Furthermore, these preclinical data indicate the generation of systemic natural killer cell activity and tumor-specific cytotoxic T lymphocyte responses. Trafficking studies confirmed that intratumorally injected Mφ/Glipr1 could migrate to draining lymph nodes. Overall, our data suggest that this novel gene-modified cell approach is an effective treatment avenue that induces antitumor immune responses in preclinical studies.

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Acknowledgements

This work was supported by the National Cancer Institute Grant R01 CA50588.

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Author notes

  1. G Yang, J Wang, A Goltsov, D Floryk & T C Thompson

    Present address: 5Current address: Department of Genitourinary Medical Oncology—Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,

Authors and Affiliations

  1. Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

    K Tabata, S Kurosaka, M Watanabe, K Edamura, T Satoh, G Yang, E Abdelfattah, J Wang, A Goltsov, D Floryk & T C Thompson

  2. Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA

    T C Thompson

  3. Department of Radiology, Baylor College of Medicine, Houston, TX, USA

    T C Thompson

  4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    T C Thompson

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  1. K Tabata
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Correspondence to T C Thompson.

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Competing interests

Some of the data included in this paper are relevant to intellectual property, co-invented by one of the authors (TCT), held by Baylor College of Medicine, and licensed to Progression Therapeutics Inc., a private biotechnology start-up.

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Tabata, K., Kurosaka, S., Watanabe, M. et al. Tumor growth and metastasis suppression by Glipr1 gene-modified macrophages in a metastatic prostate cancer model. Gene Ther 18, 969–978 (2011). https://doi.org/10.1038/gt.2011.51

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