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Modulating mammary tumor growth, metastasis and immunosuppression by siRNA-induced MIF reduction in tumor microenvironment

Cancer Gene Therapy volume 22, pages 463–474 (2015)Cite this article

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Abstract

Macrophage migration inhibitory factor (MIF) has been identified as a major gene product upregulated in breast cancer cells–tissues upon the accumulation of macrophages. However, regulatory role of MIF in tumor microenvironment is not well understood. Previously, we have developed small interfering RNA (siRNA)-loaded nanoparticle system to effectively reduce MIF expression in both breast cancer cells and macrophages. Using this nanoparticle system, in this study we demonstrated that the siRNA-induced MIF reduction in murine mammary cancer line 4T1 and human breast cancer line MDA-MB-231 resulted in significant reduction of cell proliferation and increase of apoptosis; the siRNA-induced MIF reduction in tumor-associated macrophages resulted in a significant reduction of surface expression of CD74 and CD206 and a significant increase of surface expression of major histocompatibility complex II, as well as intracellular expression of tumor necrosis factor-α and interleukin-2. A direct injection of the MIF-siRNA-loaded nanoparticles into 4T1 tumor in mice resulted in effective reduction of intratumoral MIF. This led to a reduction of tumor growth and metastasis. This also resulted in a reduction of circulating myeloid-derived suppressive cells both in number and in suppressive function. CD4 T-cell infiltration to tumor was increased. More importantly, this not only slowed the growth of treated 4T1 tumor, but also delayed the growth and metastasis of a contralateral untreated 4T1-luc tumor, suggesting the development of systemic antitumor responses. This study demonstrates for the first time that the siRNA-mediated intratumoral MIF reduction can induce antitumoral immune response via reducing systemic immune suppression.

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Acknowledgements

We thank Case Comprehensive Cancer Center-Flow Core Lab for the kind assistance and support on FACS analysis. We thank Small Animal Imaging Center of Case Western Reserve University for the kind assistance and support on imaging analysis. We also thank Professor Bingcheng Wang at School of Medicine of Case Western Reserve University for kindly providing various murine and human breast tumor lines for this study. This study was supported by CTSC (Clinical Translational Scientific Collaboration) grant of Coulter CON501510-69361 (MZ) and by Immunogene Therapy Fund from Seidman Cancer Center (JAK).

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Authors and Affiliations

  1. Department of Biomedical Engineering, Case Western Reserve University (CWRU), Cleveland, OH, USA

    M Zhang, L Yan & J A Kim

  2. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    M Zhang & J A Kim

  3. Division of Surgical Oncology, University Hospitals, Case Medical Center, Case Western Reserve University, Cleveland, OH, USA

    J A Kim

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  1. M Zhang
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Correspondence to M Zhang or J A Kim.

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Zhang, M., Yan, L. & Kim, J. Modulating mammary tumor growth, metastasis and immunosuppression by siRNA-induced MIF reduction in tumor microenvironment. Cancer Gene Ther 22, 463–474 (2015). https://doi.org/10.1038/cgt.2015.42

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