Effect Of Myeloid-derived Suppressor Cells Research Articles

Anti-inflammatory effects of myeloid-derived suppressor cells and macrophage crosstalk contribute to tumor progression (P2043)

Abstract Myeloid-Derived Suppressor Cells (MDSC) polarize macrophages (MΦ) to a Type II tumor-promoting phenotype via MDSC-MΦ crosstalk. However, the role of inflammation in MDSC-MΦ crosstalk is not well defined. To determine the role of inflammation, we utilized wild type, IL-6-/-, and IL-10-/- mice bearing syngeneic 4T1 mammary carcinoma. MΦ and 4T1-induced MDSC express IL-6 and IL-10 receptors, suggesting that they have the potential to respond to both cytokines. To determine if IL-6 and IL-10 contribute to tumor progression by modulating MDSC-MΦ crosstalk, MDSC from 4T1-bearing wild type or IL-10-/- mice were cultured with MΦ from wild type or IL-6-/- mice. MDSC were anti-inflammatory and decreased MΦ production of IL-6. IL-6 is important in vivo since 4T1-bearing IL-6-/- mice have extended survival and delayed primary tumor growth vs. wild type mice. Anti-inflammatory effects are exacerbated by MΦ themselves, since their production of IL-6 increases MDSC production of IL-10. However, MΦ-produced IL-6 affects MDSC indirectly, as exogenous IL-6 does not increase MDSC IL-10 production. Although IL-10 is classically considered as an anti-inflammatory cytokine, it contributes to tumor progression because 4T1-bearing IL-10-/- mice have delayed primary tumor growth and extended survival vs. wild type mice. These data demonstrate that MDSC have anti-inflammatory effects and that MDSC-MΦ cross-talk contributes to the overall milieu of IL-10 and IL-6 within the tumor microenvironment.

Abstract 4718: Withaferin A, a potent and abundant component of Withania somnifera root extract, reduces myeloid-derived suppressor cell function.

Abstract Myeloid cells play a crucial role in growth and metastasis of malignant tumors. Tumor infiltrating myeloid cells includes myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAMS) and dendritic cells (DC). These cells infiltrate into tumor and suppress tumor immunity by their inherent immune suppressive activity which is enhanced by interactions with each other (cross-talk). Therapeutic strategies targeting manipulation of these cells are being developed. The root extract of the plant Withania somnifera (Ashwagandha) (WRE) has been reported to reduce tumor cell proliferation and angiogenesis. Whether the anti-tumor effects of WRE are due to direct effects on malignant cells, or whether WRE also impacts immune suppressive myeloid cells is unknown. We hypothesize that WRE or its constituents impact tumor infiltrating myeloid cells and thereby boost anti-tumor immunity. HPLC and mass spectrometry analysis revealed that Withaferin A (WA) is the most abundant constituent of Withania somnifera root powder (ChromaDex, Inc. Irvine, CA). In comparison with the other constituents, WA has the most potent effect on reducing suppressive functions of myeloid cells. A prominent effect of MDSC is their production of IL-10 which increases upon cross-talk with macrophages, thus polarizing immunity to a tumor promoting type-2 phenotype. WA reduces inherent and cross-talk induced IL-10 secretion from MDSC in a dose dependent manner. Macrophage secretion of IL-6 and TNFα cytokines that are characteristic of M1-type macrophages and that also increase MDSC accumulation and function, are also reduced by WA. Much of the T cell suppressive activity of MDSC is due to MDSC production of reactive oxygen species (ROS), and WA significantly reduces MDSC production of ROS. Thus adjunctive treatment with WA has the potential to concomitantly reduce myeloid cell mediated immune suppression, to polarize immunity towards a tumor-rejecting type I phenotype, and to facilitate the development of anti-tumor immunity. Supported by NIH RO1CA115880, RO1CA84232, and American Cancer Society IRG-97-153-07 Citation Format: Pratima Sinha, Suzanne Ostrand-Rosenberg. Withaferin A, a potent and abundant component of Withania somnifera root extract, reduces myeloid-derived suppressor cell function. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4718. doi:10.1158/1538-7445.AM2013-4718

Dynamic Change and Impact of Myeloid-Derived Suppressor Cells in Allogeneic Bone Marrow Transplantation in Mice

Myeloid-derived suppressor cells (MDSCs) are a group of myeloid cells composed of hematopoietic progenitor cells, immature macrophages, dendritic cells, and granulocytes, which accumulate in inflammatory diseases and various cancers. Here, we investigated the dynamic changes and effects of MDSCs in graft-versus-host disease (GVHD) development and/or tumor relapse after syngeneic and allogeneic bone marrow transplantation (BMT). We found that adding functional MDSCs in donor graft alleviated GVHD, whereas removal of MDSCs in vivo exacerbated GVHD. After T cell-deplete BMT, MDSCs transiently accumulated in the blood and spleen of recipients without GVHD. In contrast, after T cell-replete BMT, the levels of blood MDSCs were constantly elevated in recipients with GVHD. MDSC accumulation positively correlated with the severity of GVHD. Additionally, MDSC accumulation was further increased upon tumor relapse. Although MDSCs isolated from both syngeneic and allogeneic BMT recipients inhibited T cell proliferation in response to alloantigen stimulation ex vivo, MDSCs from the recipients with GVHD showed much higher suppressive potency compared with those from recipients without GVHD. These results indicate that MDSCs can regulate the immune response in acute GVHD, and possibly tumor relapse, subsequent to allogeneic BMT.

Increased Myeloid-Derived Suppressor Cells in Gastric Cancer Correlate with Cancer Stage and Plasma S100A8/A9 Proinflammatory Proteins

Immune dysfunction may contribute to tumor progression in gastric cancer (GC) patients. One mechanism of immune dysfunction is the suppression of T cell activation and impairment of the efficacy of cancer immunotherapy by myeloid-derived suppressor cells (MDSCs). We assessed the phenotype and immunosuppressive function of MDSCs in GC patients. We further investigated the role of S100A8/A9 in GC and the relationship between S100A8/A9 and MDSC function. Lastly, the effect of MDSCs on survival rates and its potential as a prognostic factor in GC patients were investigated. MDSCs from PBMCs of GC patients were identified by comparing the expression of specific surface markers with PBMCs from healthy individuals. The ability of MDSCs to suppress T lymphocyte response and the effect of S100A8/A9 and RAGE blocking were tested in vitro by (autologous) MLR. GC patients had significantly more MDSCs than healthy individuals. These MDSCs suppressed both T lymphocyte proliferation and IFN-γ production and had high arginase-I expression. Levels of S100A8/A9 in plasma were higher in GC patients compared with healthy individuals, and they correlated with MDSC levels in the blood. Blocking of S100A8/A9 itself and the S100A8/A9 receptor RAGE on MDSCs from GC patients abrogated T cell effector function. We found that high levels of MDSCs correlated with more advanced cancer stage and with reduced survival (p = 0.006). S100A8/A9 has been identified as a potential target to modulate antitumor immunity by reversing MDSC-mediated immunosuppression.

Myeloid-derived Suppressor Cells (MDSCs) in Gliomas and Glioma-Development

Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of cells that inhibit anti-tumor immunity through a variety of mechanisms. Malignant gliomas are heavily infiltrated by myeloid cells, some of which appear to share biological functions of MDSCs. Our data with mouse de novo gliomas indicate critical roles of these cells in glioma development. This review summarizes the current understanding of MDSC biology in gliomas and discusses therapeutic interventions that can safely reverse the suppressive effects of MDSCs. The insight gained from these findings may lead to the development of novel immunotherapeutic strategies for gliomas.

Inhibition of lipopolysaccharide-induced myeloid-derived suppressor cells in the proliferation of spleen T lymphocytes

To explore the effects of lipopolysaccharide (LPS)-induced myeloid-derived suppressor cells (MDSCs) on the proliferation of spleen T lymphocytes. BALB/c mice were randomly divided into two groups: LPS group and normal control group. They were injected intraperitoneally with LPS and normal saline solution respectively. MDSCs were separated with CD11b immunomagnetic beads from the spleen extract of mice. The morphological characteristics of MDCSs were observed by Wright-Giemsa staining and the characteristic molecules on cell surface identified by flow cytometry. And the effects of MDSCs on the in vitro proliferation of T cells were determined by methyl-thiazolyl-tetrazolium bromide (MTT). The proportion of MDSCs in the spleen of the LPS group was much more than that of the normal control group (27.4% ± 6.6% vs 5.1% ± 3.8%; t = 5.06, P = 0.007). CD11b(+)Gr-1(+)MDSCs could be separated by CD11b immunomagnetic beads from the spleen of mice injected with LPS at a high purity of 84.0% ± 4.2%. MTT method showed that the proliferation of T cells decreased significantly after a co-cultivation with CD11b(+)MDSCs versus the control group. And it was positively correlated with the number of MDSCs (F = 46.26, P = 0.000). A high purity of LPS-induced myeloid-derived suppressor cells may be separated with CD11b immunomagnetic beads. And it has dose-dependent inhibitory effects on the proliferation of the spleen T lymphocytes.

Abstract 775: Sequential common gamma-chain cytokines facilitate differentiation of tumor-reactive T cells that are resistant to MDSC and can induce rejection of breast tumors

Abstract Adoptive T cell immunotherapy (AIT) utilizing ex vivo expanded HER-2/neu-specific T cells is a promising modality in the treatment of patients with breast carcinoma. Previously, our group has described the ability of tumor-sensitized T cells activated ex vivo with bryostatin 1 and ionomycin (B/I) and subsequently expanded with common γ-chain receptor family cytokines IL-2 and IL-7/IL-15 cultured in an alternating manner to induce primary breast tumor regression in FVBN202 transgenic mice. These results, however, required the combination of AIT with in vivo depletion of myeloid-derived suppressor cells (MDSCs) as the presence of these cells abrogated the anti-tumor efficacy of neu-specific lymphocytes. Presently, we report the implementation of a novel ex vivo expansion protocol, in which IL-2 and IL-7/IL-15 are cultured in a sequential manner post B/I with tumor-specific activated cells and support expansion of tumor reactive CD44+CD62L− effector T cells (TE) and CD44+CD62L+ central memory T cells (TCM). We show that tumor-specific cells activated in this manner induce rejection of primary breast tumor and provide long-term protection against the tumor, even in the presence of MDSC. Of particular interest, tumor-reactive CD4+ and CD8+ lymphocytes expanded with this method conferred resistance to the suppressive effects of MDSCs in vitro. Additionally, we demonstrate that innate immune cells are essential in eliciting tumor rejection. Flow cytometric analysis indicates Natural Killer (NK) and Natural Killer T-cell (NKT) as well as the Interferon-γ Producing Killer Dendritic Cell (IKDC) populations significantly increase following ex vivo expansion with sequential common γ-chain cytokines. Depletion of innate immune cells in adoptively transferred cells resulted in the failure of AIT to reject tumor. Together, our data suggest that sequential common γ-chain cytokines can support differentiation of tumor-reactive T cells which are resistant to MDSC, as well as innate immune cells which may be essential in supporting the anti-tumor efficacy of T cells. These results potentially provide a new paradigm in therapeutic AIT of breast carcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 775. doi:10.1158/1538-7445.AM2011-775

Inhibiting the inhibitors: evaluating agents targeting cancer immunosuppression

Importance of the field: Immunotherapy of cancer has not improved disease-free or overall patient survival. The lack of concordance between immunological and clinical responses in cancer immunotherapy trials is thought to result from the pervasive presence of tumor-driven immune suppression that allows tumor to escape and that has not been adequately targeted by current therapies.Areas covered in this review: Because multiple mechanisms of tumor induced suppression have been identified and shown to contribute to tumor escape, the opportunity arises to interfere with these mechanisms. A range of known tumor-derived inhibitors can now be blocked or neutralized by biologic or metabolic agents. Used alone or in combination with each other or with conventional cancer therapies, these agents offer novel therapeutic strategies for the control of tumor escape.What the reader will gain: This review deals with currently available inhibitors for counteracting tumor immune escape. The restoration of effective anti-tumor immunity in patients with cancer will require new approaches aiming at: i) protection of immune cells from adverse effects of myeloid-derived suppressor cells, regulatory T cells or inhibitory factors thus enhancing effector functions; and ii) prolonging survival of central memory T cells, thus ensuring long-term protection.Take home message: Inhibitors of mechanisms responsible for tumor escape could restore anti-tumor immune responses in patients with cancer.