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- 저자 : ( Tim F. Greten ) (검색결과 2 건)
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Deciphering and Reversing Immunosuppressive Cells in the Treatment of Hepatocellular Carcinoma
( Su Jong Yu ),( Tim F. Greten ) 대한간암학회 2020 대한간암학회지 Vol.20 No.1
Use of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) has been partially successful. However, most HCC patients do not respond to immunotherapy. HCC has been shown to induce several immune suppressor mechanisms in patients. These suppressor mechanisms include involvement of myeloid-derived suppressor cells, regulatory T-cells, functionally impaired dendritic cells (DCs), neutrophils, monocytes, and tumor associated macrophages. The accumulation of immunosuppressive cells may lead to an immunosuppressive tumor microenvironment as well as the dense fibrotic stroma which may contribute to immune tolerance. Our laboratory has been investigating different cellular mechanisms of immune suppression in HCC patients. In vitro as well as in vivo studies have demonstrated that abrogation of the suppressor cells enhances or unmasks tumor-specific antitumor immune responses. Two or three effective systemic therapies including ICIs and/or molecular targeted therapies and the addition of innovative combination therapies targeting immune suppressor cells may lead to increased immune recognition with a greater tumor response. We reviewed the literature for the latest research on immune suppressor cells in HCC, and here we provide a comprehensive summary of the recent studies in this field. (J Liver Cancer 2020;20:1-16)
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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 car cinoma (HCC), but lacks efficacy in advanced HCC. We inves tigated 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 hu man 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 infil trating 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 microen vironment 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.
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