肿瘤细胞治疗研究
英文原题：Three distinct mechanisms underlying human γδ T cell-mediated cytotoxicity against malignant pleural mesothelioma.
恶性胸膜间皮瘤（MPM）是一种罕见且高度侵袭性的胸部肿瘤，预后差，治疗选择有限。尽管免疫检查点抑制剂在临床试验中对部分不可切除的MPM患者显示出有希望的效果，但大多数MPM患者对目前可用的治疗仅表现出有限的缓解率。因此，迫切需要为MPM开发新颖和创新的治疗方式，包括基于免疫效应细胞的疗法。
恶性胸膜间皮瘤（MPM）是一种罕见且高度侵袭性的胸部肿瘤，预后差，治疗选择有限。尽管免疫检查点抑制剂在临床试验中对部分不可切除的MPM患者显示出有希望的效果，但大多数MPM患者对目前可用的治疗仅表现出有限的缓解率。因此，迫切需要为MPM开发新颖和创新的治疗方式，包括基于免疫效应细胞的疗法。
γδ T细胞通过tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA)和interleukin-2扩增，并通过使用基于铕螯合物的时间分辨荧光测定系统和基于荧光素酶的发光测定系统分析细胞表面标志物和对MPM的细胞毒性，在体外检测γδ T细胞的治疗潜力。结果与讨论：我们成功地从健康供体和MPM患者的外周血单个核细胞中扩增了γδ T细胞。γδ T细胞表达自然杀伤受体如NKG2D和DNAM-1，并在无抗原存在时对MPM细胞表现出中等水平的细胞毒性。加入PTA、(E)-4-hydroxy-3-methylbut-2-enyl diphosphate (HMBPP)或zoledronic acid (ZOL)可诱导γδ T细胞中TCR依赖性细胞毒性并分泌interferon-γ (IFN-γ)。此外，表达CD16的γδ T细胞在抗epidermal growth factor receptor (EGFR) mAb存在时对MPM细胞表现出显著水平的细胞毒性，其浓度低于临床设置中的浓度，而未产生可检测水平的IFN-γ。综上所述，γδ T细胞通过NK受体、TCR和CD16三种不同机制对MPM表现出细胞毒性活性。由于major histocompatibility complex (MHC)分子不参与识别，自体和异体γδ T细胞均可用于开发基于γδ T细胞的MPM过继免疫治疗。
INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rare and highly aggressive thoracic tumor with poor prognosis and limited therapeutic options. Although immune checkpoint inhibitors exhibit a promising effect in some patients with unresectable MPM in clinical trials, the majority of MPM patients show only modest response rates to the currently available treatments. It is thus imperative to develop novel and innovative therapeutic modalities for MPM, including immune effector cell-based therapies. METHODS: γδ T cells were expanded using tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) and interleukin-2, and the therapeutic potential of γδ T cells was examined through analyzing cell surface markers and cellular cytotoxicity against MPM in vitro using a europium chelate-based time-resolved fluorescence assay system and a luciferase-based luminescence assay system. RESULTS AND DISCUSSION: We successfully expanded γδ T cells from peripheral blood mononuclear cells of healthy donors and MPM patients. γδ T cells expressed natural killer receptors such as NKG2D and DNAM-1 and exhibited a moderate level of cytotoxicity to MPM cells in the absence of antigens. The inclusion of PTA, ( E )-4-hydroxy-3- methylbut-2-enyl diphosphate (HMBPP) or zoledronic acid (ZOL) induced a TCR-dependent cytotoxicity in γδ T cells and secreted interferon-γ (IFN-γ). In addition, γδ T cells expressing CD16 exhibited a significant level of cytotoxicity against MPM cells in the presence of an anti-epidermal growth factor receptor (EGFR) mAb, at lower concentrations than in clinical settings, whereas a detectable level of IFN-γ was not produced. Taken together, γδ T cells showed cytotoxic activity against MPM in three distinct mechanisms through NK receptors, TCRs and CD16. Since major histocompatibility complex (MHC) molecules are not involved in the recognition, both autologous and allogeneic γδ T cells could be used for the development of γδ T cell-based adoptive immunotherapy for MPM.
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