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细胞因子诱导的杀伤细胞作为联合免疫疗法增强对肾癌的疗效。

Increase in Efficacy of Checkpoint Inhibition by Cytokine-Induced-Killer Cells as a Combination Immunotherapy for Renal Cancer.

机构信息

Department of Integrated Oncology, CIO Bonn, University Hospital Bonn, Venusberg-Campus 1, D 53127 Bonn, Germany.

Department of Applied Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, D-53359 Rheinbach, Germany.

出版信息

Int J Mol Sci. 2020 Apr 27;21(9):3078. doi: 10.3390/ijms21093078.

DOI:10.3390/ijms21093078
PMID:32349280
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7246811/
Abstract

Cytokine-induced killer (CIK) cells are heterogeneous, major histocompatibility complex (MHC)-unrestricted T lymphocytes that have acquired the expression of several natural killer (NK) cell surface markers following the addition of interferon gamma (IFN-γ), OKT3 and interleukin-2 (IL-2). Treatment with CIK cells demonstrates a practical approach in cancer immunotherapy with limited, if any, graft versus host disease (GvHD) toxicity. CIK cells have been proposed and tested in many clinical trials in cancer patients by autologous, allogeneic or haploidentical administration. The possibility of combining them with specific monoclonal antibodies nivolumab and ipilimumab will further expand the possibility of their clinical utilization. Initially, phenotypic analysis was performed to explore CD3, CD4, CD56, PD-1 and CTLA-4 expression on CIK cells and PD-L1/PD-L2 expression on tumor cells. We further treated CIK cells with nivolumab and ipilimumab and measured the cytotoxicity of CIK cells cocultured to renal carcinoma cell lines, A-498 and Caki-2. We observed a significant decrease in viability of renal cell lines after treating with CIK cells ( < 0.0001) in comparison to untreated renal cell lines and anti-PD-1 or anti-CTLA-4 treatment had no remarkable effect on the viability of tumor cells. Using CCK-8, Precision Count Beads™ and Cell Trace™ violet proliferation assays, we proved significant increased proliferation of CIK cells in the presence of a combination of anti-PD-1 and anti-CTLA-4 antibodies compared to untreated CIK cells. The IFN-γ secretion increased significantly in the presence of A-498 and combinatorial blockade of PD-1 and CTLA-4 compared to nivolumab or ipilimumab monotreatment ( < 0.001). In conclusion, a combination of immune checkpoint inhibition with CIK cells augments cytotoxicity of CIK cells against renal cancer cells.

摘要

细胞因子诱导的杀伤(CIK)细胞是异质性的、主要组织相容性复合体(MHC)不受限制的 T 淋巴细胞,在添加干扰素γ(IFN-γ)、OKT3 和白细胞介素 2(IL-2)后获得了几种自然杀伤(NK)细胞表面标志物的表达。CIK 细胞的治疗在癌症免疫治疗中具有实用价值,其移植物抗宿主病(GvHD)毒性有限,如果有的话。CIK 细胞已通过自体、同种异体或单倍体异体给药在癌症患者的许多临床试验中提出并进行了测试。与特异性单克隆抗体纳武单抗和伊匹单抗联合使用的可能性将进一步扩大其临床应用的可能性。最初,进行表型分析以探索 CIK 细胞上的 CD3、CD4、CD56、PD-1 和 CTLA-4 表达以及肿瘤细胞上的 PD-L1/PD-L2 表达。我们进一步用纳武单抗和伊匹单抗处理 CIK 细胞,并测量 CIK 细胞与肾癌细胞系 A-498 和 Caki-2 共培养的细胞毒性。与未经处理的肾癌细胞系相比,用 CIK 细胞处理后观察到肾癌细胞系的活力显著降低(<0.0001),而抗 PD-1 或抗 CTLA-4 治疗对肿瘤细胞的活力没有显著影响。使用 CCK-8、精密计数珠™和 CellTrace™紫色增殖测定法,我们证明了在存在抗 PD-1 和抗 CTLA-4 抗体的组合的情况下,CIK 细胞的增殖显著增加,与未处理的 CIK 细胞相比。与纳武单抗或伊匹单抗单药治疗相比,在 A-498 存在下以及 PD-1 和 CTLA-4 的组合阻断下,IFN-γ 的分泌显著增加(<0.001)。总之,免疫检查点抑制与 CIK 细胞联合使用可增强 CIK 细胞对肾癌细胞的细胞毒性。

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