Sun Nai-Yun, Chen Yu-Li, Wu Wen-Yih, Lin Han-Wei, Chiang Ying-Cheng, Chang Chi-Fang, Tai Yi-Jou, Hsu Heng-Cheng, Chen Chi-An, Sun Wei-Zen, Cheng Wen-Fang
Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Cancers (Basel). 2019 Sep 19;11(9):1400. doi: 10.3390/cancers11091400.
The immuno-inhibitory checkpoint PD-L1, regulated by tumor cells and antigen-presenting cells (APCs), dampened the activation of T cells from the PD-1/PD-L1 axis. PD-L1-expressing APCs rather than tumor cells demonstrated the essential anti-tumor effects of anti-PD-L1 monotherapy in preclinical tumor models. Using the murine tumor model, we investigated whether anti-PD-L1 antibody increased the antigen-specific immune response and anti-tumor effects induced by the antigen-specific protein vaccine, as well as the possible mechanisms regarding activation of APCs. Anti-PD-L1 antibody combined with the PEK protein vaccine generated more potent E7-specific immunity (including the number and cytotoxic activity of E7-specific cytotoxic CD8 T lymphocytes) and anti-tumor effects than protein vaccine alone. Anti-PD-L1 antibody enhanced the maturation of dendritic cells and the proportion of M1-like macrophages in tumor-draining lymph nodes and tumors in tumor-bearing mice treated with combinatorial therapy. PD-L1 blockade overturned the immunosuppressive status of the tumor microenvironment and then enhanced the E7 tumor-specific antigen-specific immunity and anti-tumor effects generated by an E7-specific protein vaccine through modulation of APCs in an E7-expressing small tumor model. Tumor-specific antigen (like HPV E7 antigen)-specific immunotherapy combined with APC-targeting modality by PD-L1 blockade has a high translational potential in E7-specific cancer therapy.
免疫抑制检查点PD-L1受肿瘤细胞和抗原呈递细胞（APC）调控，可通过PD-1/PD-L1轴抑制T细胞的激活。在临床前肿瘤模型中，表达PD-L1的APC而非肿瘤细胞显示出抗PD-L1单药治疗的关键抗肿瘤作用。利用小鼠肿瘤模型，我们研究了抗PD-L1抗体是否能增强抗原特异性蛋白疫苗诱导的抗原特异性免疫反应和抗肿瘤作用，以及激活APC的可能机制。与单独的蛋白疫苗相比，抗PD-L1抗体联合PEK蛋白疫苗产生了更强的E7特异性免疫（包括E7特异性细胞毒性CD8 T淋巴细胞的数量和细胞毒性活性）和抗肿瘤作用。在联合治疗的荷瘤小鼠中，抗PD-L1抗体增强了肿瘤引流淋巴结和肿瘤中树突状细胞的成熟以及M1样巨噬细胞的比例。在表达E7的小肿瘤模型中，PD-L1阻断通过调节APC，颠覆了肿瘤微环境的免疫抑制状态，进而增强了E7特异性蛋白疫苗产生的E7肿瘤特异性抗原特异性免疫和抗肿瘤作用。肿瘤特异性抗原（如HPV E7抗原）特异性免疫疗法联合通过PD-L1阻断靶向APC的方式在E7特异性癌症治疗中具有很高的转化潜力。
