Myeloid-Derived Suppressor Cell Inhibition of the IFN Response in Tumor-Bearing Mice

Abstract

Our group and others have determined that immune effector cells from patients with advanced cancers exhibit reduced activation of IFN signaling pathways. We hypothesized that increases in immune regulatory cells termed myeloid derived suppressor cells (MDSC) could interfere with the host immune response to tumors by inhibiting immune cell responsiveness to interferons. The C26 murine adenocarcinoma model was employed to study immune function in advanced malignancy. C26 bearing mice had significantly elevated levels of GR1+CD11b+ MDSC as compared to control mice, and splenocytes from tumor bearing mice exhibited reduced phosphorylation of STAT1 (P-STAT1) on Tyr 701 in response to IFN alpha or IFN gamma. This inhibition was seen in splenic CD4+ and CD8+ T cells as well as NK cells. In vitro co culture experiments revealed that MDSC inhibited the IFN responsiveness of splenocytes from normal mice. Treatment of C26 bearing mice with gemcitabine or an anti-GR1 antibody led to depletion of MDSC and restored splenocyte IFN responsiveness. Spleens from C26 bearing animals displayed elevated levels of iNOS protein and nitric oxide (NO). In vitro treatment of splenocytes with a nitric oxide donor led to a decreased STAT1 IFN response. The elevation in NO in C26 bearing mice was associated with increased levels of nitration on STAT1. Finally, splenocytes from iNOS knockout mice bearing C26 tumors exhibited a significantly elevated IFN-response as compared to control C26 tumor bearing mice. These data suggest that NO produced by MDSC can lead to reduced interferon responsiveness in immune cells.

Myeloid-Derived Suppressor Cells Attenuate TH1 Development through IL-6 Production to Promote Tumor Progression

“…MDSC-induced loss of STAT1 activation in response to IFN-a or IFN-g has been reported in a murine adenocarcinoma model (46), further supporting a link between IFN-g signaling and MDSC-derived IL-6. The IFN-g-STAT1 signaling regulates its downstream transcriptional factor, T-bet, which is a critical step in T H 1 differentiation (47).…”

Highly cytotoxic natural killer cells are associated with poor prognosis in patients with cutaneous T-cell lymphoma

“…It is also possible that there may be additional immunosuppressive mechanisms that are present in the microenvironment of CTCL patients. For example, previous studies by our group and others have demonstrated alterations in NK-cell signaling because of the presence of suppressive myeloid cells such as myeloid-derived suppressor cells and tumor-associated macrophages in cancer patients, 26 and both populations have been reported among CTCL patients. [27][28][29] Additional checkpoint inhibitors, such as PD-1, CTLA-4, TIGIT, and TIM-3 may also play a role in decreasing NK-cell function in patients, because previous studies demonstrated that these inhibitors may be increased in the presence of IL-15.…”

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

“…reduce the efficacy of immunotherapies by impairing antigen presentation and T cell activation. [26][27][28] We found that MDSCs were a good biomarker of metastatic disease and presented a potent prognostic marker for NKT cell activation therapy. Based on circulating levels of MDSCs, we could track responses to NKT cell activation therapy and identify mice that relapsed.…”

“…24 MDSCs can directly suppress CD4 C and CD8 C T cell responses, and indirectly promote immune suppression through the induction of FoxP3 C regulatory T cells. [25][26][27][28] Therefore, immunotherapeutic strategies that target both tumor cells and MDSCs are of particular interest. Given that NKT cells have been shown to regulate MDSC-mediated immune suppression during viral infection, 29 the role of NKT cell activation on cancer-associated immunosuppression requires further investigation.…”