细胞因子释放综合征来源的IL-6介导JAK/STAT3通路在弥漫大B淋巴瘤逃逸CAR-T杀伤中的作用及机制

临床上靶向CD19嵌合抗原受体T细胞(CART19)治疗弥漫大B淋巴瘤后部分出现疾病进展。新近发现弥漫大B淋巴瘤细胞IL-6/JAK/STAT3活化者进展快。前期比较CART19治疗前和治疗后进展标本发现进展标本IL-6/JAK/STAT3高度活化且合并细胞因子释放综合征(CRS)，血清IL-6明显升高，提示CRS来源的IL-6在介导JAK/STAT3活化中起重要作用。预实验表明，进展标本PD-L1表达增强且增殖快和易转移。本项目先验证CART19治疗后进展样本中IL-6/JAK/STAT3活化情况，利用小鼠模型、免疫印迹、单细胞技术、流式质谱等阐明CRS来源的IL-6介导JAK/STAT3活化中的作用及通过上调淋巴瘤细胞PD-L1、Survivin, Bcl-xl,VEGF, WASF等逃逸杀伤的新机制，为阐明淋巴瘤细胞逃逸CART19杀伤新机制提供实验依据，为发现新型治疗靶点奠定基础。

Some patients with diffused large B cell lymphoma will progress after CD19-targeted chimeric antigen receptor T cells (CART19s) therapy in clinic. Recent researches found that progressed diffused large B cell lymphoma usually have highly activated IL-6/JAK/STAT3 pathway and these patients often complicated with cytokine release syndrome (CRS) with elevated IL-6 in serum implying that CRS-derived IL-6 play important roles in mediating JAK/STAT3 pathway activation. Our preliminary data found that progressed lymphoma cells express high levels of PD-L1 with high proliferation and easily metastasis. The current study will first verify the activation of IL-6/JAK/STAT3 pathway. Next we will clarify the roles and mechanisms of CRS-derived IL-6 in JAK/STAT3 pathway activation. The research can lay the foundation for novel mechanisms of lymphoma cells escaped from CART19 therapy. And also the research will provide novel targets for the treatment.