Syk激酶调控外周T细胞淋巴瘤PD-L1表达的分子机制及相关联合用药研究

目前临床上针对外周T细胞淋巴瘤（PTCL）尚无标准治疗策略，总体治愈率低，预后差。Syk激酶在多种类型PTCL肿瘤组织存在高表达，但是其在PTCL异位高表达后，所参与调控的上下游通路尚未完全阐明，且Syk激酶是否可作为PTCL治疗的新方向仍有待进一步验证。课题组将依托丰富的临床样本资源及体内外实验模型，深入阐述Syk激酶异位高表达后诱导PTCL发生的分子机制。前期研究结果提示：1）中国不同病理类型PTCL患者肿瘤组织中广泛存在Syk激酶高表达；2）下调Syk激酶活性仅可部分抑制PTCL肿瘤生长，且不同PTCL对于Syk抑制剂的反应性存在明显差异；3）转录组测序及免疫共沉淀结果证实Syk激酶可通过下游互作底物SHIP1调控肿瘤细胞表面PD-L1表达；4）靶向胞膜PD-L1及胞浆Syk激酶的联合用药方案可有效抑制肿瘤细胞增殖活性。因此，本课题开展有望为PTCL患者的临床靶向药物选择提供新方向。

At present, there is no standard strategy for the treatment of peripheral T-cell lymphoma (PTCL), resulting in poor outcomes and 5-year overall survival. Syk kinase is highly expressed in many types of PTCL tumor tissues, but related molecular pathogenesis of PTCL remain poorly understood. We investigate the role of Syk in the pathogenesis of T-cell lymphoid malignancies base on the clinical sample resources and in vitro and in vivo experimental models. The preliminary results suggest that down-regulation of Syk kinase activity can only partially inhibit the growth of PTCL tumors and different PTCL models exhibit sensitivity towards Syk inhibitor treatment. RNA-Seq and co-immunoprecipitation analysis demonstrated that Syk kinase could regulate PD-L1 expression through the regulation of SHIP1 activity. The combination of Syk inhibitor and anti-PD-L1 antibody synergistically inhibit proliferation activity of tumor cells. Therefore, our results provide a new direction for the treatment of PTCL patients.