MYD88基因调控ICOS/ICOSL轴促进调节性T细胞介导弥漫性大B细胞淋巴瘤多淋巴结外器官浸润的机制研究

淋巴瘤是全球十大高发肿瘤，弥漫性大B细胞淋巴瘤是最常见的病理亚型，多淋巴结外器官浸润是其独立不良预后因素，属治疗难点，但其分子机制尚不明确。申请人的前期研究显示多淋巴结外器官浸润患者存在：①高频的MYD88基因突变；②显著的免疫抑制微环境状态，表现为ICOS/ICOSL轴介导的调节性T细胞（Treg）浸润。MYD88L265P热点突变在患者及转染的淋巴瘤细胞株/免疫细胞共培养体系内均与ICOS及ICOSL表达显著上调及Treg细胞升高有关。基于以上发现，申请人提出科学假设：MYD88基因突变诱导淋巴瘤细胞ICOSL表达，与T细胞ICOS结合，促进Treg介导的肿瘤细胞广泛结外浸润、播散，引起化疗耐药。本课题为相关工作的延续和深化，从患者肿瘤、细胞株和动物模型深入研究MYD88基因如何调控ICOS/ICOSL轴促进Treg细胞介导肿瘤免疫逃逸的分子机制，为开展新型靶向治疗奠定理论基础。

Lymphoma is among the world's top ten cancers. Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of lymphoma, and multiple extranodal involvement is an independent prognostic factor, with unilluminated molecular mechanism. The applicant's previous study showed that patients with multiple extranodal involvement had: (1) high-frequency of MYD88 mutations and (2) significant immunosuppressive microenvironmental status, manifested by regulatory T cell (Treg) infiltration mediated by ICOS/ICOSL axis. MYD88 L265P hot spot mutation was associated with significantly upregulated ICOS/ICOSL expression and Treg cells in both patients and co-culture system of lymphoma cell lines and immune cells. Based on the above findings, the applicant proposed the scientific hypothesis: MYD88 mutation induced the expression of ICOSL in lymphoma cells, which bound to ICOS expressed on T-cells, and promoted the Treg-mediated extensive extranodal infiltration and dissemination of tumor cells, causing chemo-resistance and poor prognosis. This study is the continuation of previous related work, and is planned to illuminate the molecular mechanism of multiple extranodal involvement in DLBCL mediated by the activation of Tregs through ICOS/ICOSL axis regulated by MYD88, from patients’ tumor samples, to lymphoma cell lines and animal models. This study also aims to explore the theoretical basis for novel targeted therapy.