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Abstract：
BACKGROUND: Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and lymphoepithelioma-like carcinoma of the lung, have been linked to EBV infection. Currently, several TCR-T-cell therapies for EBV-associated tumors are in clinical trials, but due to the suppressive immune microenvironment of solid tumors, the clinical application of TCR-T-cell therapy for EBV-associated solid tumors is limited. Figuring out the mechanism by which EBV participates in the formation of the tumor immunosuppressive microenvironment will help T cells or TCR-T cells break through the limitation and exert stronger antitumor potential.
METHODS: Flow cytometry was used for analyzing macrophage differentiation phenotypes induced by EBV-infected and EBV-uninfected tumors, as well as the function of T cells co-cultured with these macrophages. Xenograft model in mice was used to explore the effects of M2 macrophages, TCR-T cells, and matrix metalloprotein 9 (MMP9) inhibitors on the growth of EBV-infected tumors.
RESULTS: EBV-positive tumors exhibited an exhaustion profile of T cells, despite the presence of a large T-cell infiltration. EBV-infected tumors recruited a large number of mononuclear macrophages with CCL5 and induced CD163+M2 macrophages polarization through the secretion of CSF1 and the promotion of autocrine IL10 production by mononuclear macrophages. Massive secretion of MMP9 by this group of CD163+M2 macrophages induced by EBV infection was an important factor contributing to T-cell exhaustion and TCR-T-cell therapy resistance in EBV-positive tumors, and the use of MMP9 inhibitors improved the function of T cells cocultured with M2 macrophages. Finally, the combination of an MMP9 inhibitor with TCR-T cells targeting EBV-positive tumors significantly inhibited the growth of xenografts in mice.
CONCLUSIONS: MMP9 inhibitors improve TCR-T cell function suppressed by EBV-induced M2 macrophages. TCR-T-cell therapy combined with MMP9 inhibitors was an effective therapeutic strategy for EBV-positive solid tumors.
METHODS: Flow cytometry was used for analyzing macrophage differentiation phenotypes induced by EBV-infected and EBV-uninfected tumors, as well as the function of T cells co-cultured with these macrophages. Xenograft model in mice was used to explore the effects of M2 macrophages, TCR-T cells, and matrix metalloprotein 9 (MMP9) inhibitors on the growth of EBV-infected tumors.
RESULTS: EBV-positive tumors exhibited an exhaustion profile of T cells, despite the presence of a large T-cell infiltration. EBV-infected tumors recruited a large number of mononuclear macrophages with CCL5 and induced CD163+M2 macrophages polarization through the secretion of CSF1 and the promotion of autocrine IL10 production by mononuclear macrophages. Massive secretion of MMP9 by this group of CD163+M2 macrophages induced by EBV infection was an important factor contributing to T-cell exhaustion and TCR-T-cell therapy resistance in EBV-positive tumors, and the use of MMP9 inhibitors improved the function of T cells cocultured with M2 macrophages. Finally, the combination of an MMP9 inhibitor with TCR-T cells targeting EBV-positive tumors significantly inhibited the growth of xenografts in mice.
CONCLUSIONS: MMP9 inhibitors improve TCR-T cell function suppressed by EBV-induced M2 macrophages. TCR-T-cell therapy combined with MMP9 inhibitors was an effective therapeutic strategy for EBV-positive solid tumors.
摘要：
背景：EB病毒（EBV）是一种双链DNA致癌病毒。几种类型的实体瘤，如鼻咽癌，EBV相关性胃癌,和淋巴上皮瘤样肺癌，与EBV感染有关.目前,几种用于EBV相关肿瘤的TCR-T细胞疗法正在临床试验中，但是由于实体瘤的免疫抑制免疫微环境，TCR-T细胞治疗EBV相关实体瘤的临床应用有限.阐明EBV参与肿瘤免疫抑制微环境形成的机制将有助于T细胞或TCR-T细胞突破限制并发挥更强的抗肿瘤潜力。
方法：流式细胞术用于分析EBV感染和未感染EBV的肿瘤诱导的巨噬细胞分化表型，以及与这些巨噬细胞共培养的T细胞的功能。小鼠异种移植模型用于探讨M2巨噬细胞的作用,TCR-T细胞,和基质金属蛋白9（MMP9）抑制剂对EBV感染的肿瘤生长的影响。
结果：EBV阳性肿瘤表现出T细胞耗竭特征，尽管存在大量T细胞浸润。EBV感染的肿瘤招募了大量带有CCL5的单核巨噬细胞，并通过分泌CSF1和促进单核巨噬细胞产生自分泌IL10来诱导CD163M2巨噬细胞极化。EBV感染诱导该组CD163+M2巨噬细胞大量分泌MMP9是导致EBV阳性肿瘤T细胞耗竭和TCR-T细胞治疗抵抗的重要因素,MMP9抑制剂的使用改善了与M2巨噬细胞共培养的T细胞的功能。最后,MMP9抑制剂与靶向EBV阳性肿瘤的TCR-T细胞的组合显著抑制小鼠异种移植物的生长。
结论：MMP9抑制剂可改善EBV诱导的M2巨噬细胞抑制的TCR-T细胞功能。TCR-T细胞疗法联合MMP9抑制剂是EBV阳性实体瘤的有效治疗策略。
方法：流式细胞术用于分析EBV感染和未感染EBV的肿瘤诱导的巨噬细胞分化表型，以及与这些巨噬细胞共培养的T细胞的功能。小鼠异种移植模型用于探讨M2巨噬细胞的作用,TCR-T细胞,和基质金属蛋白9（MMP9）抑制剂对EBV感染的肿瘤生长的影响。
结果：EBV阳性肿瘤表现出T细胞耗竭特征，尽管存在大量T细胞浸润。EBV感染的肿瘤招募了大量带有CCL5的单核巨噬细胞，并通过分泌CSF1和促进单核巨噬细胞产生自分泌IL10来诱导CD163M2巨噬细胞极化。EBV感染诱导该组CD163+M2巨噬细胞大量分泌MMP9是导致EBV阳性肿瘤T细胞耗竭和TCR-T细胞治疗抵抗的重要因素,MMP9抑制剂的使用改善了与M2巨噬细胞共培养的T细胞的功能。最后,MMP9抑制剂与靶向EBV阳性肿瘤的TCR-T细胞的组合显著抑制小鼠异种移植物的生长。
结论：MMP9抑制剂可改善EBV诱导的M2巨噬细胞抑制的TCR-T细胞功能。TCR-T细胞疗法联合MMP9抑制剂是EBV阳性实体瘤的有效治疗策略。
