Functional Changes in Myeloid-Derived Suppressor Cells (MDSCs) during Tumor Growth: FKBP51 Contributes to the Regulation of the Immunosuppressive Function of MDSCs

Abstract

Myeloid-derived suppressor cells (MDSCs) are increased by tumor-derived factors and suppress anti-tumor immunity. MDSCs obtained at a late time point after tumor injection had stronger suppressive activity than MDSCs obtained at an early time point, as measured by T cell proliferation assays. To find factors in MDSCs that change during tumor growth, we analyzed gene expression profiles from MDSCs at different time points after tumor injection. We found that immune response-related genes were downregulated but protumor function-related genes were upregulated in both monocytic MDSCs (Mo-MDSCs) and polymorphonuclear granulocytic MDSCs (PMN-MDSCs) at the late time point. Among differentially expressed genes, FK506 binding protein 51 (FKBP51), which is a member of the immunophilin protein family and plays a role in immunoregulation, was increased in the Mo-MDSCs and PMN-MDSCs isolated from the late time points. Experiments using small interfering RNA and a chemical inhibitor of FKBP51 revealed that FKBP51 contributes to the regulation of the suppressive function of MDSCs by increasing inducible NO synthase, arginase-1, and reactive oxygen species levels and enhancing NF-κB activity. Collectively, our data suggest that FKBP51 is a novel molecule that can be targeted to regulate the immunosuppressive function of MDSCs.

Immune evasion in cancer: Mechanistic basis and therapeutic strategies

“…In support of this, inhibition of Tregs by monoclonal antibodies has been shown to decrease tumor development [134,135]. In addition, other regulatory cell populations such as MDSCs which accumulate in spleen, blood, tumors, and bone marrow of tumor-bearing mice and cancer patients [136,137] have been considered as important targets for therapeutic intervention [138]. MDSCs secrete IL-10 and TGF-␤ and enhance angiogenesis and metastasis by inducing Treg production [23,139].…”

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

“…37 In contrast, NKT cells suppresses MDSC accumulation during viral infection, 29 and activated NKT cells can induce MDSC differentiation into DCs. 29,46,57,58 In expanded memory T cell cultures, an increased number of mouse CD49b C T cells or human CD161 C T cells reduced the suppressive effects of MDSCs, leading to enhanced IFNg production in response to tumor antigens. 45,58 Although these studies did not use markers that allow definitive identification of NKT cells, they are consistent with our findings that activated NKT cells rescued T cell proliferation from MDSC mediated suppression.…”

Mechanisms of intimate and long-distance cross-talk between glioma and myeloid cells: How to break a vicious cycle

“…After prolonged contact with glioma cells microglia seem to lose their phagocytic properties. Moreover, it was reported that MDSCs associated with advanced stage disease show stronger suppressive properties than MDSCs occurring early in murine breast cancer models [224]. Down-regulation of transcription of immune response-related genes as well as an up-regulation of tumourpromoting genes in MDSCs was detected at a late time point of tumourigenesis.…”

“…Down-regulation of transcription of immune response-related genes as well as an up-regulation of tumourpromoting genes in MDSCs was detected at a late time point of tumourigenesis. In this study, FKBP51 -a cis-trans prolylisomerase that binds to the immunosuppressant FK506 and rapamycin -was identified to play an important role in the regulation of the suppressive functions of MDSCs [224].…”