靶向细胞因子诱导的杀伤细胞与髓系来源抑制细胞在肝癌中的相互作用。
Targeting the crosstalk between cytokine-induced killer cells and myeloid-derived suppressor cells in hepatocellular carcinoma.
机构信息
Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
出版信息
J Hepatol. 2019 Mar;70(3):449-457. doi: 10.1016/j.jhep.2018.10.040. Epub 2018 Nov 9.
BACKGROUND & AIMS: Cytokine-induced killer (CIK) cell-based immunotherapy is effective as an adjuvant therapy in early stage hepatocellular carcinoma (HCC) but lacks efficacy in advanced HCC. We aimed to investigate immune suppressor mechanisms in HCC, focusing on the role of myeloid-derived suppressor cells (MDSCs) in response to CIK therapy.
METHODS
MDSCs were quantified by flow cytometry and quantitative real-time PCR. Cytokines were detected by cytokine array. A lactate dehydrogenase 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 in subcutaneous and orthotopic tumor models in C57BL/6 and BALB/c mice. The antitumor effects of human CIKs and MDSCs were also tested in vitro.
RESULTS
Adoptive cell transfer of CIKs 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 antitumor activity in 2 different HCC models. MDSCs efficiently suppressed the cytotoxic activity of CIKs in vitro. In contrast, treatment with a PDE5 inhibitor reversed the 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 antitumor efficacy. Similar results were observed when human CIKs were tested in vitro in the presence of CD14HLA-DR MDSCs. Treatment of MDSCs with a PDE5 inhibitor suppressed MDSC suppressor function and enhanced CIK activity against human HCC cell lines in vitro.
CONCLUSION
Our results suggest that targeting MDSCs is an efficient strategy to enhance the antitumor efficacy of CIKs for the treatment of patients with HCC.
LAY SUMMARY
Cytokine-induced killer cells are a mixture of immune cells given to eliminate cancer cells. However, not all patients respond to this treatment. Herein, we show in 2 different liver cancer models that myeloid-derived suppressor cells are increased in response to cytokine-induced killer cell therapy. Targeting these myeloid-derived suppressor cells may provide an additional therapeutic benefit alongside cytokine-induced killer cell therapy.
背景与目的
细胞因子诱导的杀伤（CIK）细胞免疫疗法作为早期肝细胞癌（HCC）的辅助治疗是有效的，但在晚期 HCC 中缺乏疗效。我们旨在研究 HCC 中的免疫抑制机制，重点研究髓源抑制细胞（MDSC）在 CIK 治疗中的作用。
方法
通过流式细胞术和实时定量 PCR 定量 MDSC。通过细胞因子阵列检测细胞因子。在存在或不存在 MDSC 的情况下进行乳酸脱氢酶细胞毒性测定，以研究 CIK 对体外 HCC 细胞的杀伤作用。使用 FDA 批准的 PDE5 抑制剂他达拉非在体外和体内靶向 MDSC。在 C57BL/6 和 BALB/c 小鼠的皮下和原位肿瘤模型中测试了两种不同的鼠 HCC 细胞系。还在体外测试了人 CIK 和 MDSC 的抗肿瘤作用。
结果
将 CIK 过继转移到荷瘤小鼠中，诱导肿瘤微环境中的炎症介质（例如，CX3CL1、IL-13）和肿瘤浸润性 MDSC 的增加，导致 2 种不同 HCC 模型中的抗肿瘤活性受损。MDSC 可有效抑制 CIK 的细胞毒性作用。相比之下，PDE5 抑制剂的治疗通过 ARG1 和 iNOS 阻断逆转了 MDSC 抑制功能，全身给予 PDE5 抑制剂可防止 CIK 细胞治疗时 MDSC 在肿瘤微环境中的积聚，并增加其抗肿瘤疗效。当体外存在 CD14HLA-DR MDSC 时，用人 CIK 进行的类似实验也得到了类似的结果。PDE5 抑制剂处理 MDSC 可抑制 MDSC 抑制功能并增强 CIK 对体外人 HCC 细胞系的活性。
结论
我们的研究结果表明，针对 MDSC 是增强 CIK 治疗 HCC 患者抗肿瘤疗效的有效策略。
概要
细胞因子诱导的杀伤细胞是一组免疫细胞，用于消除癌细胞。然而，并非所有患者对此治疗均有反应。在此，我们在 2 种不同的肝癌模型中显示，髓系抑制性细胞在细胞因子诱导的杀伤细胞治疗后增加。针对这些髓系抑制性细胞可能会为细胞因子诱导的杀伤细胞治疗提供额外的治疗益处。
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