Abstract 3661: Crucial roles of cytokine-signaling for alteration in functions of myeloid-derived suppressor cells

Abstract

Abstract Various types of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) were generated from immature myeloid cells (ImCs) according to the state of tumor microenvironments. In human cancer patients, MDSCs are generally defined as monocytic (CD11b+, CD14+, and HLA-DR-/low) or granulocytic (CD11b+ and CD15+) myeloid cells with antitumor and immunosuppressive activities. In order to develop the effective cancer immunotherapy, these immune suppressor populations should be restrictlly controlled in tumor bearing hosts. In the present research, we evaluated the immunological functions of monocytic or granulocytic myeloid cells, which were collected from tumor tissues of colorectal cancer patients. We found here that myeloid populations in tumor tissues significantly induced immuno-modulating factors such as IL-6, IL-10, VEGF, iNOS, ARG1, IDO1, and IDO2. In addition, we confirmed that tumor-infiltrating myeloid-populations exhibited a significant immunosuppressive activity than those prepared from peripheral blood mononuclear cells (PBMCs). To investigate how tumor-infiltrating MDSCs acquired the immunosuppressive activity, we focused on the effect of tumor-derived factors (TDFs) on immunosuppressive activity. PBMCs from healthy volunteers were cultured in the presence of IL-6, TGF-β, and granulocyte macrophage colony-stimulating factor (GM-CSF) for 6 days, and then differentiated into Mo-MDSCs (CD11b+CD14+CD33+)-like phenotype cells. The generated Mo-MDSCs were further isolated by using cell sorter system and cultured with donor matched T cells and stimulated with anti-CD3/CD28 beads for 3 days. As a result, we confirmed that T cell proliferation was significantly inhibited by the addition of Mo-MDSCs generated with IL-6, TGF-β and GM-CSF. On the other hand, these populations showed immunostimulating ability in the presence of IFN-g in vitro, suggesting the Mo-MDSCs might have multi-differencing potentials. These results indicated that tumor-infiltrating MDSCs acquired stronger immunosuppressive activity by tumor-derived IL-6 and TGF-β, however the function might be altered in response to cytokine conditions. Thus, we concluded that IL-6 and TGF-β induced functional maturation of MDSCs in tumor microenvironments, suggesting promising targets to improve the immunological responses by immunotherapy for cancer patients. Citation Format: Kentaro Sumida, Yosuke Ono, Junya Ohtake, Kazutaka Masuko, Satoshi Terada, Shun Kaneumi, Takuto Kishikawa, Toshiyuki Kita, Hidemitsu Kitamura. Crucial roles of cytokine-signaling for alteration in functions of myeloid-derived suppressor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3661. doi:10.1158/1538-7445.AM2014-3661