It has been shown that tumors have developed numerous ways to escape tumor specific immune responses. These mechanisms will ultimately not only enhance tumor growth, but also impair the effect of immune based therapies in cancer. Myeloid derived suppressor cells represent a recently identified cell population, which has been shown to impair tumor specific immune responses both in mice and human. MDSC can be divided in two subtypes (namely monocytic and granulocytic MDSC. We have been able to examine and define the regulation and function of murine MDSC by IFN-gamma and studied MDSC in different HCC models 1. We described a new IFN-gamma -dependent regulator mechanism of the suppressor function of MDSC. While IFN-gamma blockade impairs the suppressor function of monocytic CD11b+Gr-1dull/int. it has opposing effects on granulocytic CD11b+Gr-1high MDSC. Co-culture of CD11b+Gr-1high granulocytic MDSC with antigen-stimulated T cells and simultaneous blockade of IFN-gamma by the use of anti-IFN-gamma blocking antibody, IFN-gamma-/- effector T cells, IFN-gammaR-/- MDSC or STAT1 -/- MDSC led to up-regulation of Bcl2a1 in CD11b+Gr-1high granulocytic MDSC, improved survival of granulocytic subpopulation during MDSC-T cell interaction and enhanced suppressor function. Molecular studies revealed that GM-CSF released by antigen-stimulated CD8+T cells induced Bcl2a1 up-regulation, which was repressed in the presence of IFN-gamma by a direct interaction of phosphorylated STAT-1 with the Bcl2a1 promotor. Bcl2a1 overexpressing MDSC not only demonstrated prolonged survival in vitro and enhanced suppressor function in vitro but also showed improved suppressor function in vivo. Our data suggest that IFN-gamma/ STAT1 -dependent regulation of Bcl2a1 regulates survival and thereby suppressor function of CD11b+Gr-1high MDSC. 2. Myeloid derived suppressor cells (MDSC) are immature myeloid cells with immunosuppressive activity. They accumulate in tumor-bearing mice and humans with different types of cancer, including hepatocellular carcinoma (HCC). We examined the biology of MDSC in murine HCC models and to identify a model, which mimics the human disease. An accumulation of MDSC was found in mice with HCC irrespectively of the model tested. Transplantable tumors rapidly induced systemic recruitment of MDSC, in contrast to slow-growing DEN-induced or MYC-expressing HCC, where MDSC numbers only increased intra-hepatically in mice with advanced tumors. MDSC derived from mice with subcutaneous tumors were more suppressive than those from mice with DEN-induced HCC. Enhanced expression of genes associated with MDSC generation (GM-CSF, VEGF, IL-6, IL-1beta) and migration (MCP-1, KC, S100A8, S100A9) was observed in mice with subcutaneous tumors. In contrast, only KC levels increased in mice with DEN-induced HCC. Both KC and GM-CSF over-expression or anti-KC and anti-GM-CSF treatment controlled MDSC frequency in mice with HCC. Finally, the frequency of MDSC decreased upon successful anti-tumor treatment with sorafenib. Conclusions: Our data indicate that MDSC accumulation is a late event during hepatocarcinogenesis and differs significantly depending on the tumor model studied.

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National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Ma, Chi; Kesarwala, Aparna H; Eggert, Tobias et al. (2016) NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531:253-7
Ji, Juling; Eggert, Tobias; Budhu, Anuradha et al. (2015) Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma. Hepatology 62:481-95
Gamrekelashvili, Jaba; Greten, Tim F; Korangy, Firouzeh (2015) Immunogenicity of necrotic cell death. Cell Mol Life Sci 72:273-83
Kapanadze, Tamar; Medina-Echeverz, José; Gamrekelashvili, Jaba et al. (2015) Tumor-induced CD11b(+) Gr-1(+) myeloid-derived suppressor cells exacerbate immune-mediated hepatitis in mice in a CD40-dependent manner. Eur J Immunol 45:1148-58
Medina-Echeverz, José; Eggert, Tobias; Han, Miaojun et al. (2015) Hepatic myeloid-derived suppressor cells in cancer. Cancer Immunol Immunother 64:931-40
Medina-Echeverz, José; Ma, Chi; Duffy, Austin G et al. (2015) Systemic Agonistic Anti-CD40 Treatment of Tumor-Bearing Mice Modulates Hepatic Myeloid-Suppressive Cells and Causes Immune-Mediated Liver Damage. Cancer Immunol Res 3:557-66
Medina-Echeverz, José; Haile, Lydia A; Zhao, Fei et al. (2014) IFN-γ regulates survival and function of tumor-induced CD11b+ Gr-1high myeloid derived suppressor cells by modulating the anti-apoptotic molecule Bcl2a1. Eur J Immunol 44:2457-67
Eggert, Tobias; Medina-Echeverz, José; Kapanadze, Tamar et al. (2014) Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage. PLoS One 9:e112717
Kapanadze, Tamar; Gamrekelashvili, Jaba; Ma, Chi et al. (2013) Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma. J Hepatol 59:1007-13
Ma, Chi; Kapanadze, Tamar; Gamrekelashvili, Jaba et al. (2012) Anti-Gr-1 antibody depletion fails to eliminate hepatic myeloid-derived suppressor cells in tumor-bearing mice. J Leukoc Biol 92:1199-206

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