PET显像监测顺铂对三阴性乳腺癌中PD-L1表达的调控及引导联合免疫治疗的研究

三阴性乳腺癌（TNBC）易复发和转移，恶性程度较高，严重危害人们的健康。由于缺少相应靶向药物，化疗是目前治疗TNBC的主要手段，但预后较差。已有研究表明，靶向PD-1/PD-L1的免疫治疗可有效延长TNBC患者生存期，预后与患者PD-L1表达水平相关，但整体响应率不高。前期工作中我们发现顺铂可诱导TNBC细胞PD-L1表达升高，这为TNBC的治疗提供了新思路。本项目拟利用顺铂诱导TNBC高表达PD-L1，然后联合Pembrolizumab抗体协同治疗，一方面能增强顺铂的化疗效果，另一方面可逆转对免疫治疗不响应或者进一步增强有响应患者的疗效，提高整体治疗效果。同时借助前期获得的靶向PD-L1非竞争结合性PET显像探针（[68Ga]NOTA-Nb109），实时、在体检测PD-L1表达的动态变化，筛选有效目标，引导优化联合治疗方案，评估治疗效果，阐明联合用药机制，实现分子影像指导下的精准治疗。

Triple-negative breast cancer (TNBC) has seriously damaged people’s health owing to its high risk of recurrence and metastasis. It often follows a poor prognosis with the main therapeutic approach of chemotherapy because of the lack of targeting drugs. Several clinical trials have demonstrated that targeting programmed death/ligand-1(PD-1/PD-L1) immunotherapy could prolong the survival time of patients and the prognosis is related to the expression level of PD-L1 in patients, while the overall response rate is low. In our preliminary works, we found that cisplatin could induce PD-L1 upregulation in TNBC cells, which provides a new sight for treatment of TNBC. In the project, we intend to use cisplatin to induce PD-L1 overexpression in TNBC and then combination with immunotherapy for a synergistic effect. On one hand, it could enhance the chemotherapeutic effects of cisplatin; On the other hand, it could reverse the low efficacy of immunotherapy in non-responsive patients and further enhance the efficacy in responsive patients. Meanwhile, the dynamic expression of PD-L1 in tumor will be assessed real-timely and noninvasively with a highly PD-L1 specific non-blocking PET imaging probe ([68Ga]NOTA-Nb109) for screening the target responsive groups, guiding the optimal treatment project, evaluating the therapeutic effects, elucidating the mechanism of combination therapy and achieving the imaging-guided precise therapy.