miR155 通过 PD-1/PD-L1 介导的淋巴瘤细胞与 CD8+T 细胞相互作用使 B 细胞淋巴瘤细胞对抗 PD-L1 抗体敏感。
MiR155 sensitized B-lymphoma cells to anti-PD-L1 antibody via PD-1/PD-L1-mediated lymphoma cell interaction with CD8+T cells.
机构信息
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, 197 Rui Jin Er Road, Shanghai, 200025, China.
Department of Laboratory Medicine, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
出版信息
Mol Cancer. 2019 Mar 30;18(1):54. doi: 10.1186/s12943-019-0977-3.
BACKGROUND
MicroRNAs (miRs) are involved in lymphoma progression by regulating tumor cell interaction with microenvironment. MiR155 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological effect on tumor microenvironment needs to be futher investigated.
METHODS
MiR155 was detected by quantitative real-time PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR155 on lymphoma progression and tumor microenvironment was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model.
RESULTS
Serum miR155 was significantly elevated, correlated with tumor miR155 expression, and indicated poor disease outcome in DLBCL. MiR155 overexpression was associated with decreased peripheral blood CD8+T cells and inhibition of T-cell receptor signaling. Of note, EBV-positive patients showed higher serum miR155 than EBV-negative patients. In co-culture systems of B-lymphoma cells with immune cells, miR155 induced Fas-mediated apoptosis of CD8+T cells, which could be targeted by anti-PD-1 and anti-PD-L1 antibodies. Moreover, miR155 enhanced lymphoma cell PD-L1 expression, recruited CD8+T cells by PD-1/PD-L1 interaction and inhibited CD8+T cell function via dephosphorylating AKT and ERK. MiR155-induced AKT/ERK inactivation was more obvious in CD8+T cells co-cultured with EBV-infected B-lymphoma cells. In vivo in a murine xenograft model established with subcutaneous injection of A20 cells, PD-L1 blockade particularly retarded miR155-overexpressing tumor growth, consistent with maintenance of CD8+T cells and their function.
CONCLUSIONS
As a oncogenic biomarker of B-cell lymphoma, serum miR155 was related to lymphoma progression through modulating PD-1/PD-L1-mediated interaction with CD8+T cells of tumor microenvironment, indicating the sensitivity of B-cell lymphoma to PD-L1 blockade. Also CD8+T cells could be a therapeutic mediator of immune checkpoint inhibitors in treating EBV-associated lymphoid malignancies.
背景
MicroRNAs（miRs）通过调节肿瘤细胞与微环境的相互作用参与淋巴瘤的进展。miR155 在弥漫性大 B 细胞淋巴瘤（DLBCL）中过表达，其对肿瘤微环境的生物学效应需要进一步研究。
方法
采用实时定量 PCR 检测新诊断的 DLBCL 患者血清 miR155。在 B 淋巴瘤细胞系中体外及在小鼠异种移植模型中体内检测 miR155 对淋巴瘤进展和肿瘤微环境的作用机制。
结果
血清 miR155 明显升高，与肿瘤 miR155 表达相关，并提示 DLBCL 预后不良。miR155 过表达与外周血 CD8+T 细胞减少和 T 细胞受体信号转导抑制有关。值得注意的是，EBV 阳性患者的血清 miR155 高于 EBV 阴性患者。在 B 淋巴瘤细胞与免疫细胞的共培养系统中，miR155 诱导 CD8+T 细胞 Fas 介导的凋亡，可被抗 PD-1 和抗 PD-L1 抗体靶向。此外，miR155 增强淋巴瘤细胞 PD-L1 的表达，通过 PD-1/PD-L1 相互作用招募 CD8+T 细胞，并通过去磷酸化 AKT 和 ERK 抑制 CD8+T 细胞功能。在与 EBV 感染的 B 淋巴瘤细胞共培养的 CD8+T 细胞中，miR155 诱导的 AKT/ERK 失活更为明显。在皮下注射 A20 细胞建立的小鼠异种移植模型中，PD-L1 阻断尤其延缓了 miR155 过表达肿瘤的生长，与 CD8+T 细胞的维持及其功能一致。
结论
作为 B 细胞淋巴瘤的致癌生物标志物，血清 miR155 通过调节肿瘤微环境中 PD-1/PD-L1 介导的与 CD8+T 细胞的相互作用与淋巴瘤进展相关，表明 B 细胞淋巴瘤对 PD-L1 阻断的敏感性。此外，CD8+T 细胞可能是治疗 EBV 相关淋巴恶性肿瘤的免疫检查点抑制剂的治疗介导物。
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