miR21/miR155-FOXO1轴调控CD8+T细胞介导复发难治弥漫大B细胞淋巴瘤免疫逃逸的机制研究

Diffuse large B-cell lymphoma (DLBCL) is a major subtype of aggressive lymphoma. Patients with DLBCL usually present with rapid progress and poor prognosis. Dysregulation of tumor microenvironment plays a key role in the progression of relapse refractory (R/R) DLBCL. Our previous study demonstrated that miR21/miR155 were upregulated in R/R DLBCL, which regulated immune checkpoints signaling pathway in tumor microenvironment. Recent studies showed that FOXO1 (Forkhead box O1) could affect tumor immunity through modulating proliferation, differentiation and homing of CD8+T cells. Our study manifested that miR21/miR155 could target FOXO1 and negatively correlated with FOXO1 expression. Based on previous results , the aim of this study is to clarify the relationship between miR21/miR155-FOXO1 axis and CD8+T cells exhaustion in immune escape and disease progression, further exploring the therapeutic potential of immune checkpoints inhibitors and developing targeted therapy strategy in lymphoma.

弥漫大B细胞淋巴瘤（DLBCL）是侵袭性淋巴瘤的重要类型，疾病进展迅速，预后差。复发难治DLBCL的肿瘤微环境异常是影响淋巴瘤发生进展的关键因素。前期研究发现miR21/miR155在复发难治弥漫大B细胞淋巴瘤中血清中显著高表达，通过调控肿瘤微环境免疫检查点通路异常介导肿瘤免疫逃逸。FOXO1基因在介导肿瘤免疫细胞增殖、分化和归巢中扮演着极为重要的作用，通过影响CD8+T细胞调控肿瘤免疫。前期结果提示miR21/miR155靶向FOXO信号通路关键基因FOXO1并且两者表达呈负相关。本课题为前期工作的延伸和深化，将进一步阐明miR21/miR155-FOXO1轴的调控机制，证实复发难治DLBCL中miR21/miR155-FOXO1轴与CD8+T细胞耗竭介导肿瘤免疫逃逸和疾病进展的内在联系，研究免疫检查点抑制剂等非化疗药物的潜力，为淋巴瘤免疫靶向治疗奠定理论基础。

本课题旨在阐释B细胞淋巴瘤中特定分子标志调控肿瘤微环境信号通路改变、肿瘤增殖、凋亡及化疗敏感性的具体作用机制。通过分析相关细胞信号通路的活化程度，研究肿瘤微环境相关改变。目前取得重要进展包括：1、基于4个循环miRNA的新型弥漫大B细胞淋巴瘤预后模型：MDSCs和Th17细胞在淋巴瘤复发中的作用。2、miR130b通过OX40/OX40L信号通路介导Th17细胞和淋巴瘤细胞相互作用提高OX40免疫调控点抑制剂的抗淋巴瘤作用。3、乙型肝炎病毒相关滤泡性淋巴瘤呈现T细胞相关炎症表型并对来那度胺更敏。以上研究为基于B细胞淋巴瘤患者的分子异质性制定靶向治疗分层提供理论支撑，创新的提出复发难治B细胞淋巴瘤患者的免疫治疗新策略