肿瘤细胞治疗研究
英文原题：EBV promotes TCR-T-cell therapy resistance by inducing CD163+M2 macrophage polarization and MMP9 secretion.
EBV promotes TCR-T-cell therapy resistance by inducing CD163+M2 macrophage polarization and MMP9 secretion.
MMP9 抑制剂可改善受 EBV 诱导的 M2 巨噬细胞抑制的 TCR-T 细胞功能。
背景：Epstein-Barr 病毒（EBV）是一种双链 DNA 致癌病毒。鼻咽癌、EBV 相关胃癌和肺淋巴上皮瘤样癌等多种实体瘤均与 EBV 感染相关。目前，针对 EBV 相关肿瘤的多种 TCR-T 细胞疗法正在临床试验中，但实体瘤免疫抑制性微环境限制了其临床应用。阐明 EBV 参与形成肿瘤免疫抑制微环境的机制，有助于 T 细胞或 TCR-T 细胞突破这一限制并发挥更强抗肿瘤潜力。方法：采用流式细胞术分析 EBV 感染及未感染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 细胞功能。采用小鼠异种移植模型探究 M2 巨噬细胞、TCR-T 细胞和基质金属蛋白酶 9（MMP9）抑制剂对 EBV 感染肿瘤生长的影响。结果：尽管 EBV 阳性肿瘤中 T 细胞浸润量较大，仍表现出 T 细胞耗竭特征。EBV 感染肿瘤募集大量单核细胞，并通过分泌 CSF1 及促进单核细胞自分泌 IL-10，诱导其向 CD163+M2 巨噬细胞极化。这些 EBV 诱导的 CD163+M2 巨噬细胞大量分泌 MMP9，是导致 EBV 阳性肿瘤中 T 细胞耗竭和 TCR-T 治疗耐药的重要因素；使用 MMP9 抑制剂可改善与 M2 巨噬细胞共培养的 T 细胞功能。最后，MMP9 抑制剂联合靶向 EBV 阳性肿瘤的 TCR-T 细胞，显著抑制了小鼠异种移植瘤生长。结论：MMP9 抑制剂可改善 EBV 诱导的 M2 巨噬细胞对 TCR-T 细胞功能的抑制。TCR-T 细胞疗法联合 MMP9 抑制剂是治疗 EBV 阳性实体瘤的有效策略。
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.
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