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Depletion of myeloid-derived suppressor cells during interleukin-12 immunogene therapy does not confer a survival advantage in experimental malignant glioma

Cancer Gene Therapy volume 21, pages 38–44 (2014)Cite this article

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Abstract

Myeloid-derived suppressor cells (MDSCs) accumulate in the glioma microenvironment during tumor progression and promote immunosuppression. Interleukin-12 (IL-12) immunogene therapy can alter MDSCs toward an antigen-presenting cell phenotype and these mature cells can have a central role in antigen presentation. It remains unclear, however, how MDSC depletion can affect glioma immunotherapy. In this study, we generated a replication-deficient adenoviral vector, Ad.5/3.cRGD-mIL12p70, that transduces the GL261-based murine glioma cell line, resulting in the induction of biologically active, murine IL12p70 expression. Ex vivo, IL-12 expressed by GL261 cells induced interferon-γ synthesis in CD8+ T cells (P<0.001), CD4+ T cells (P=0.009) and natural killer cells (P=0.036). When injected 1 week after tumor implantation, Ad.5/3.cRGD-mIL12p70 successfully prolonged the survival of glioma-bearing mice. Sixty percent of animals treated with IL-12 immunotherapy were long-term survivors over 175 days, whereas all the control group animals expired by 40 days after tumor implantation (P=0.026). Mice receiving Ad.5/3.cRGD-mIL12p70 also accumulated 50% less MDSCs in the brain than the control group (P=0.007). Moreover, in the IL-12 group, MDSCs significantly overexpressed CD80 and major histocompatibility complex class II molecules (P=0.041). Depletion of MDSCs with Gr1+ antibody had no survival benefit induced by IL-12-mediated immunotherapy. Of note, IL-12 therapy increased the presence of myeloid dendritic cells (mDCs) in the glioma microenvironment (P=0.0069). Ultimately, the data show that in the context of IL-12 immunogene therapy, MDSCs are dispensable and mDCs may provide the majority of antigen presentation in the brain.

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Acknowledgements

This work was supported by the NCI (R01CA122930, R01CA138587) and the National Institute of Neurological Disorders and Stroke (U01NS069997, F32NS073366, K99NS082381).

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Authors and Affiliations

  1. The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA

    B Thaci, A U Ahmed, I V Ulasov, D A Wainwright, P Nigam, B Auffinger, A L Tobias, Y Han, L Zhang, K-S Moon & M S Lesniak

  2. Department of Neurosurgery, Chonnam National University Hwasun Hospital and Medical School, Jeollanam-do, Korea

    K-S Moon

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  1. B Thaci
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Correspondence to M S Lesniak.

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Thaci, B., Ahmed, A., Ulasov, I. et al. Depletion of myeloid-derived suppressor cells during interleukin-12 immunogene therapy does not confer a survival advantage in experimental malignant glioma. Cancer Gene Ther 21, 38–44 (2014). https://doi.org/10.1038/cgt.2013.81

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