肿瘤细胞治疗研究
英文原题：Demonstration of the Antitumor Activity of the iNKT Agonist ABX196, a Novel Enhancer of Cancer Immunotherapy, in Melanoma and Hepatocarcinoma Mouse Models.
本研究表明，ABX196单独使用以及与抗PD-1抗体联合使用，具有作为克服免疫抑制微环境和产生抗肿瘤活性的新策略的潜力。
未标注：免疫检查点阻断剂（ICB）通过阻断免疫抑制通路，为抗肿瘤免疫治疗提供了一种有前景的方法。合成糖脂ABX196是恒定自然杀伤T细胞（iNKT）的有效刺激剂，iNKT是一小部分调节性淋巴细胞，激活后是免疫力的强大增强因子。在携带黑色素瘤B16F10肿瘤细胞和原位Hepa 1-6肝细胞癌（HCC）细胞的C57BL/6小鼠模型中，研究了ABX196单独使用以及与化疗和ICB联合使用。在黑色素瘤模型中，免疫反应评估包括免疫荧光染色和流式细胞术检测，以识别抗CD45、抗CD8、抗CD4、抗CD3、抗CD19、抗FoxP3、CD1d四聚体和抗程序性细胞死亡蛋白1（PD-1）标志物。在HCC模型中，使用MRI、肝脏重量和IHC染色检测CD4、CD8、F4/80、PD-1、程序性死亡配体1、Ki67和FoxP3标志物来分析抗肿瘤反应。ABX196与抗PD-1联合治疗产生了显著的协同抗肿瘤效应，表现为黑色素瘤小鼠肿瘤中CD8+细胞增加以及CD8+效应细胞与FoxP3+调节性T细胞（Treg）比率的升高。ABX196单药治疗和联合治疗在HCC模型中均产生了抗肿瘤效应。由于任一治疗均具有高应答水平，单药治疗与联合治疗之间未显示出显著的生存差异。当测量外周血中的IFNγ时，明显的协同联合效应显现，表明iNKT细胞持续激活。在两种模型中，抗肿瘤效应均与肿瘤内产生更有利的T效应细胞与Treg细胞比例相关，这可能促进原本处于无反应状态的细胞增殖和积聚。概要：本研究利用小鼠黑色素瘤和HCC肿瘤模型，证明ABX196单药及与抗PD-1抗体联合使用，作为克服免疫抑制微环境并产生抗肿瘤活性的新策略具有潜力。
UNLABELLED: Immune checkpoint blockers (ICB) provide a promising approach to antitumor immunotherapy through blockade of immunosuppressive pathways. The synthetic glycolipid, ABX196, is a potent stimulator of invariant natural killer T cells (iNKT), a small subset of regulatory lymphocytes, which are powerful enhancers of immunity when activated. ABX196 was investigated alone and in combination with chemotherapy and ICBs in a melanoma B16F10 tumor cell-bearing and an orthotopic Hepa 1-6 hepatocarcinoma (HCC) cell-bearing C57BL/6 mice model. In the melanoma model, immune response evaluation included immunofluorescence staining and detection by flow cytometry to identify anti-CD45, anti-CD8, anti-CD4, anti-CD3, anti-CD19, anti-FoxP3, CD1d tetramer, and anti-programmed cell death protein 1 (PD-1) markers. Analysis by MRI, liver weight, and IHC staining to detect CD4, CD8, F4/80, PD-1, programmed death-ligand 1, Ki67, and FoxP3 markers were used to measure antitumor response in the HCC model. Combination treatment with ABX196 and anti-PD-1 resulted in significant synergistic antitumor effects, reflected by the increase of CD8+ cells in the tumor and an increased ratio of CD8+ effector cells to FoxP3+ regulatory T cells (Treg) in mice with melanomas. ABX196 monotherapy and combination therapy resulted in antitumor effects in the HCC model. No significant differences in survival were demonstrated between monotherapy and combination therapy due to high response levels with either treatment. A synergistic combination effect was apparent when IFNγ was measured in peripheral blood, indicating sustained activation of iNKT cells. In both models, the antitumor effects were associated with a generation of a more advantageous T-effector to Treg cell ratio within the tumor, which could lead to in the proliferation and accumulation of cells that would otherwise be anergized. SYNOPSIS: Using melanoma and HCC tumor models in mice, this study demonstrates the potential of ABX196, alone and in combination with anti-PD-1 antibody, as a novel strategy to overcome the immunosuppressive microenvironment and to produce antitumor activity.
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