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( Su Jong Yu ),( Chi Ma ),( Bernd Heinrich ),( Zachary J. Brown ),( Milan Sandhu ),( Qianfei Zhang ),( Qiong Fu ),( David Agdashian ),( Firouzeh Korangy ),( Tim F. Greten ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1
Aims: Cytokine-induced killer (CIK) cell-based immunotherapy is effective as adjuvant therapy in early stage hepatocellular carcinoma (HCC), but lacks efficacy in advanced HCC. We investigated immune suppressor mechanisms and focused on CIKs and myeloid-derived suppressor cells (MDSCs). Methods: MDSCs were quantified by flow cytometry, PCR, and immunohistochemistry. Cytokines were detected by cytokine array. LDH cytotoxicity assay was performed in the presence or absence of MDSCs to study CIK function against HCC cells in vitro. An FDA approved PDE5 inhibitor, tadalafil, was used to target MDSCs in vitro and in vivo. Two different murine HCC cell lines were tested as subcutaneous and orthotopic tumor models in C57BL/6 and BALB/c mice. Anti-tumor effects of human CIK and MDSC were tested in vitro. Results: Adoptive cell transfer of CIK cells into tumor bearing mice induced inflammatory mediators (e.g., CX3CL1, IL-13) in the tumor microenvironment and an increase of tumor infiltrating MDSCs leading to impaired anti-tumor activity in two different HCC tumor models. MDSCs efficiently suppressed the cytotoxic activity of CIK cells in vitro. In contrast, treatment with a PDE5 inhibitor reversed MDSC suppressor function via ARG1 and iNOS blockade and systemic treatment with a PDE5 inhibitor prevented MDSC accumulation in the tumor microenvironment upon CIK cell therapy and increased its anti-tumor efficacy. Similar results were seen when human CIK cells were tested in vitro in the presence of CD14+HLA-DR<sup>-/low</sup> MDSCs. Treatment of MDSCs with a PDE5 inhibitor suppressed MDSCs suppressor function and enhanced CIK activity against human HCC cell lines in vitro. Conclusions: Our results suggest that targeting MDSCs is an efficient strategy to enhance the antitumor efficacy of CIK cells for the treatment of patients with HCC.