虽然PD-1抗体已经在部分晚期NSCLC中跃居一线治疗，但其临床有效率仍不足20%。PD-1抗体耐药是其疗效有限的主要原因。一项Ibrutinib联合PD-1抗体治疗晚期NSCLC的II期临床研究结果初步提示：Ibrutinib可以逆转PD-1抗体耐药，协同提高PD-1抗体疗效。我们前期工作发现：①PD-1抗体在晚期NSCLC中的耐药与MDSCs上调相关；②PD-1抗体在晚期NSCLC中通过STAT3-NF-kB-IDO通路上调MDSCs诱导耐药。本研究拟通过晚期NSCLC患者临床资料分析证实MDSCs与PD-1抗体耐药相关性；利用体外细胞学实验和体内小鼠模型探讨Ibrutinib调控MDSCs数量和功能从而逆转PD-1抗体治疗晚期NSCLC耐药的机制。分别从临床患者、体外细胞水平、体内小鼠荷瘤模型三个层面揭示Ibrutinib在逆转PD-1抗体治疗晚期NSCLC耐药中的作用及调控机制。

PD-1 antibody immunotherapy has been the first-line treatment in some sorts of NSCLC, while the ORR was still lower than 20%. The resistance of the PD-1 antibody is the main mechanism of the limited efficiency. A phase II study of the combination regimen of Ibrutinib plus PD-1 antibody is ongoing in US. The preliminary result showed that: The Ibutinib could reverse the resistance of PD-1 antibody on NSCLC to enhance the anti-tumor efficiency. Our previous study conduced the resistance of PD-1 antibody was related to the up-regulation of MDSCs after the immunotherapy and the resistance of the immunotherapy was up regulated by the STAT3-NF-kB-IDO pathway. We are trying to conduct this study to confirm the relevance of PD-1 antibody resistance and the up-regulation of MDSCs in NSCLC patients. We will study the mechanism of the Ibrutinib regulation on MDSCs to reverse the PD-1 antibody resistance from in vitro cell culture system and from in vivo mouse model. Finally we will study from the patients, the in vitro cell level and the in vivo mouse model to uncover the function and the regulation mechanism of Ibrutinib on MDSCs to reverse the resistance on PD-1 antibody, respectively.