靶向治疗 miR130b 通过 OX40/OX40L 介导的与 Th17 细胞的相互作用来抵抗弥漫性大 B 细胞淋巴瘤的进展。
Therapeutic targeting miR130b counteracts diffuse large B-cell lymphoma progression via OX40/OX40L-mediated interaction with Th17 cells.
机构信息
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China.
State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, National Research Center for Translational Medicine at Shanghai, Shanghai Jiao Tong University, Shanghai, China.
出版信息
Signal Transduct Target Ther. 2022 Mar 18;7(1):80. doi: 10.1038/s41392-022-00895-2.
MicroRNAs (miRNAs) are involved in lymphoma progression by regulating the tumor microenvironment. Serum miR130b is overexpressed in diffuse large B-cell lymphoma (DLBCL), inducing Th17 cell alterations. To further illustrate its biological significance and therapeutic rationale, miR130b was detected by quantitative real-time PCR in the serum samples of 532 newly diagnosed DLBCL patients. The mechanism of miR130b on lymphoma progression and the tumor microenvironment was investigated both in vitro and in vivo. Therapeutic targeting miR130b was also evaluated, including OX40 agonistic antibody and lipid nanoparticles (LNPs)-miR130b antagomir. The results showed that serum miR130b significantly correlated with tumor miR130b and serum interleukin-17, indicating lymphoma relapse and inferior survival of DLBCL patients. MiR130b overexpression altered tumor microenvironment signaling pathways and increased Th17 cell activity. As mechanism of action, miR130b downregulated tumor OX40L expression by directly targeting IFNAR1/p-STAT1 axis, recruiting Th17 cells via OX40/OX40L interaction, thereby promoting immunosuppressive function of Th17 cells. In co-culture systems of B-lymphoma cells with immune cells, miR130b inhibited lymphoma cell autophagy, which could be counteracted by OX40 agonistic antibody and LNPs-miR130b antagomir. In murine xenograft model established with subcutaneous injection of A20 cells, both OX40 agonistic antibody and LNPs-miR130b antagomir remarkably inhibited Th17 cells and retarded miR130b-overexpressing tumor growth. In conclusion, as an oncogenic biomarker of DLBCL, miR130b was related to lymphoma progression through modulating OX40/OX40L-mediated lymphoma cell interaction with Th17 cells, attributing to B-cell lymphoma sensitivity towards OX40 agonistic antibody. Targeting miR130b using LNPs-miR130b antagomir could also be a potential immunotherapeutic strategy in treating OX40-altered lymphoid malignancies.
微小 RNA（miRNAs）通过调节肿瘤微环境参与淋巴瘤的进展。血清 miR130b 在弥漫性大 B 细胞淋巴瘤（DLBCL）中过度表达，诱导 Th17 细胞改变。为了进一步阐明其生物学意义和治疗原理，通过定量实时 PCR 检测了 532 例新诊断的 DLBCL 患者血清样本中的 miR130b。在体外和体内研究了 miR130b 对淋巴瘤进展和肿瘤微环境的作用机制。还评估了针对 miR130b 的治疗靶向，包括 OX40 激动性抗体和脂质纳米颗粒（LNPs）-miR130b 反义寡核苷酸。结果表明，血清 miR130b 与肿瘤 miR130b 和血清白介素-17 显著相关，表明 DLBCL 患者的淋巴瘤复发和生存不良。miR130b 的过表达改变了肿瘤微环境信号通路并增加了 Th17 细胞的活性。作为作用机制，miR130b 通过直接靶向 IFNAR1/p-STAT1 轴下调肿瘤 OX40L 表达，通过 OX40/OX40L 相互作用招募 Th17 细胞，从而促进 Th17 细胞的免疫抑制功能。在 B 淋巴瘤细胞与免疫细胞的共培养系统中，miR130b 抑制淋巴瘤细胞自噬，而 OX40 激动性抗体和 LNPs-miR130b 反义寡核苷酸可以拮抗这种作用。在皮下注射 A20 细胞建立的小鼠异种移植模型中，OX40 激动性抗体和 LNPs-miR130b 反义寡核苷酸均显著抑制 Th17 细胞并延缓 miR130b 过表达肿瘤的生长。总之，作为 DLBCL 的致癌生物标志物，miR130b 通过调节 OX40/OX40L 介导的淋巴瘤细胞与 Th17 细胞的相互作用与淋巴瘤进展有关，导致 B 细胞淋巴瘤对 OX40 激动性抗体敏感。使用 LNPs-miR130b 反义寡核苷酸靶向 miR130b 也可能是治疗 OX40 改变的淋巴恶性肿瘤的潜在免疫治疗策略。
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