NSCLC细胞通过XDH调控肿瘤相关巨噬细胞嘌呤代谢介导免疫抑制作用的研究

非小细胞肺癌（NSCLC）进展和转移与肿瘤微环境密切相关。肿瘤相关巨噬细胞（TAMs）是肿瘤微环境中一种重要的免疫调节细胞，抑制抗肿瘤免疫反应。申请人前期研究发现NSCLC组织中巨噬细胞较癌旁巨噬细胞高表达PD-L1，进一步分析发现NSCLC细胞高分泌CXCL8，CXCL8显著促进巨噬细胞PD-L1表达，同时上调嘌呤代谢关键酶XDH，阻断XDH能够明显下调PD-L1表达。因此，推测NSCLC细胞通过分泌CXCL8作用于巨噬细胞，激活XDH通路调控TAMs嘌呤代谢，进而上调PD-L1表达介导TAMs免疫抑制作用，促进NSCLC进展。本研究拟采用流式细胞术、RNA-Seq等技术分析NSCLC细胞对巨噬细胞免疫抑制的调控作用，阻断XDH通路进一步探讨嘌呤代谢途径介导PD-L1上调的分子机制，联合靶向XDH及PD-L1逆转TAMs免疫抑制作用，为NSCLC患者治疗提供新的措施与手段。

The progression and metastasis of non-small cell of lung cancer (NSCLC) are closely related to the tumor microenvironment. Tumor-associated macrophages (TAMs) are the important regulatory immune cells in the tumor microenvironment, which can inhibit the anti-tumor immune responses. The previous study showed that the expression of PD-L1 on NSCLC tissue-derived macrophages was significantly higher than that on peritumor tissue-derived macrophages. NSCLC cells can produce high level of CXCL8. CXCL8 derived from NSCLC cells can promote PD-L1 upregulation, as well as XDH expression in TAMs, the key enzyme for purine metabolism. Blockade of XDH signaling pathway could decrease the expression of PD-L1 in TAMs. Therefore, we hypothesis that NSCLC cells can produce CXCL8 to upregulate PD-L1 expression in TAMs via XDH activation and purine metabolism, which further making an immunosuppressive tumor microenvironment and tumor progression of NSCLC. This study is to evaluate the impact of NSCLC cells on the immunosuppression of macrophages by using flow cytometry and RNA-Seq, et al. The use of XDH blockade could further give a way to the molecular mechanisms of PD-L1 upregulation in TAMs via purine metabolism. Finally, anti-XDH antibody combined with anti-PD-L1 antibody will reverse the immunosuppression of TAMs in order to find a novel measurement for the treatment of NSCLC.