Abstract

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.IFN-gamma induced STAT1 phosphorylation in both MDSC subsets, which led to NOS2 expression in CD11b+Gr-1dull/int monocytic MDSC and enhanced suppression of T cell proliferation. In sharp contrast, the suppressor function of CD11b+Gr-1high granulocytic MDSC was enhanced in the absence of IFN-gamma using IFN-gR-/- MDSC or IFN-gamma-/- effector cells, which led to upregulation of Bcl2a1 and improved survival of the granulocytic subpopulation during MDSC-T cell interaction. Likewise Bcl2a1 overexpression in CD11b+Gr-1high granulocytic MDSC supported their suppressor activity. Thus, depending on the local IFN-gamma concentration, STAT1 regulates the function of MDSC subsets antithetically so that these two cell populations can substitute each other and suppress antigen-specific T cell immunity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011345-03
Application #
8553121
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2012
Total Cost
$224,562
Indirect Cost

  Institution

Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Ma, Chi; Han, Miaojun; Heinrich, Bernd et al. (2018) Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360:
Eggert, Tobias; Greten, Tim F (2017) Tumor regulation of the tissue environment in the liver. Pharmacol Ther 173:47-57
Eggert, Tobias; Wolter, Katharina; Ji, Juling et al. (2016) Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression. Cancer Cell 30:533-547
Ma, Chi; Kesarwala, Aparna H; Eggert, Tobias et al. (2016) NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531:253-7
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
Gamrekelashvili, Jaba; Greten, Tim F; Korangy, Firouzeh (2015) Immunogenicity of necrotic cell death. Cell Mol Life Sci 72:273-83
Medina-Echeverz, José; Eggert, Tobias; Han, Miaojun et al. (2015) Hepatic myeloid-derived suppressor cells in cancer. Cancer Immunol Immunother 64:931-40
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
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
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

Showing the most recent 10 out of 14 publications