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Particulate ?-glucan regulates the immunosuppression of granulocytic myeloid-derived suppressor cells by inhibiting NFIA expression.

ABSTRACT: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of cells which comprise two subsets: granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs). MDSCs involve in tumor-associated immune suppression by remarkably blocking effector T-cell activation and inducing expansion of regulatory T cells in the tumor microenvironment. The treatment that alters the suppression of MDSCs can effectively facilitate the antitumor immune responses. Recently, we showed that the whole ?-glucan particles (WGPs) are capable of altering the suppression of MDSCs. However, the regulatory mechanism of MDSCs by WGP remains unknown. In this study, we found that the expression of nuclear factor I-A (NFIA), an integral transcriptional component of myeloid differentiation and lineage commitment, was inhibited by WGP in G-MDSCs. The effect of WGP on expression of NFIA was the c-jun molecule dependent via Dectin-1 pathway in vitro. Moreover, NFIA knockdown could alter the suppressive function of G-MDSCs, promote the antitumor immune responses and delay the tumor progression in tumor-bearing mice. Taken together, our results demonstrate a critical role of NFIA during WGP regulating the immunosuppression of G-MDSCs, with potential implications as an antitumor immune therapeutic approach.

SUBMITTER: Tian X

PROVIDER: S-EPMC4570107 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Particulate β-glucan regulates the immunosuppression of granulocytic myeloid-derived suppressor cells by inhibiting NFIA expression.

Tian Xinyu X Tian Jie J Tang Xinyi X Rui Ke K Zhang Yue Y Ma Jie J Wang Yungang Y Xu Huaxi H Lu Liwei L Wang Shengjun S

Oncoimmunology 20150701 9

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of cells which comprise two subsets: granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs). MDSCs involve in tumor-associated immune suppression by remarkably blocking effector T-cell activation and inducing expansion of regulatory T cells in the tumor microenvironment. The treatment that alters the suppression of MDSCs can effectively facilitate the antitumor immune responses. Recently, we showed that the whole β-glucan par ...[more]

PMID: 26405609

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Project description:The presence of tumor infiltrating lymphocytes (TILs) is associated with a longer overall survival in advanced stage epithelial ovarian cancer. Despite the prognostic impact of TILs, response to checkpoint-inhibitors and antigen-specific active immunotherapy is limited in ovarian cancer. The goal of our study was to investigate the interaction between ovarian cancer and the innate and adaptive immune system in the ID8-fLuc syngeneic ovarian cancer mouse model. For the in vivo experiments C57BL/6, B6.129S7-Rag1tm1Mom/J, and B6.129P2(SJL)-Myd88tm1.1Defr/J mice were inoculated with ID8-fLuc. In vivo depletion experiments were performed using clodronate liposomes (CL), anti-CD8a, anti-GR1, anti-colony stimulating factor 1 (anti-CSF1), and TMβ1 (anti-CD122). Immune read out was performed by fluorescent activated cell sorting analysis for effector T cells, regulatory T cells, natural killer cells, B cells, macrophages, and myeloid derived suppressor cells (MDSC), immunohistochemistry for MDSC and tumor-associated macrophages (TAM) and immunofluorescence for M1 and M2 TAM in the vascular context. The effect of MDSC on T cell proliferation and phenotype were studied in vitro. We discovered that the absence of T and B cells did not influence tumor growth or survival of B6.129S7-Rag1tm1Mom/J mice compared to immunocompetent C57BL/6 mice. CL-induced macrophage depletion promoted tumor proliferation and shortened survival in C57BL/6 mice (p = 0.004) and in B6.129S7-Rag1tm1Mom/J mice (p = 0.0005). During CL treatment, we observed a clear increase of pro-inflammatory cytokines (p ≤ 0.02) and monocytic MDSC (p ≤ 0.01). Selective depletion of MDSC by anti-GR1 improved survival, certainly in comparison to mice treated with anti-CSF1 (p = 0.01-median survival 91 vs. 67.5 days). B6.129P2(SJL)-Myd88tm1.1Defr/J mice displayed to a longer median survival compared to C57BL/6 mice (90 vs. 76 days). MDSC activated by ID8-fLuc conditioned medium or ascites of tumor-bearing mice showed T cell suppressive functions in vitro. Based on these findings, we conclude that the adaptive immune system does not efficiently control tumor growth in the ID8-fLuc model. In addition, we discovered a prominent role for MDSC as the driver of immunosuppression in the ID8-fLuc ovarian cancer mouse model.

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Particulate ?-glucan regulates the immunosuppression of granulocytic myeloid-derived suppressor cells by inhibiting NFIA expression.

Publications

Particulate β-glucan regulates the immunosuppression of granulocytic myeloid-derived suppressor cells by inhibiting NFIA expression.

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