title: Modulating mammary tumor growth, metastasis and immunosuppression by siRNA-induced MIF reduction in tumor microenvironment.
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.
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University (CWRU), Cleveland, OH, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University (CWRU), Cleveland, OH, USA.
authors.forename: L
authors.initials: L
authors.lastname: Yan
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University (CWRU), Cleveland, OH, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.|Division of Surgical Oncology, University Hospitals, Case Medical Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Kim
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D037181:Lectins, C-Type / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D053758:Nanoparticles; D009362:Neoplasm Metastasis; D034741:RNA, Small Interfering / Q000235:genetics*; D000067492:RNAi Therapeutics / Q000379:methods; D011956:Receptors, Cell Surface / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics / Q000276:immunology; D059016:Tumor Microenvironment / Q000235:genetics* / Q000276:immunology
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D037181:Lectins, C-Type; D008263:Macrophage Migration-Inhibitory Factors; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C045084:invariant chain