肿瘤细胞可通过结合免疫检查点蛋白，抑制T细胞激活，从而逃避免疫杀伤。程序性死亡蛋白-1（PD-1）与配体PD-L1之间的相互作用是其中一条关键的免疫抑制信号通路。基于单克隆抗体技术的PD-1抑制剂已在多种肿瘤适应症中取得了良好的治疗效果，但是目前的抗体药物仍然存在成本高、周期长、易引发免疫相关不良反应等问题。核酸适配体是一类具有识别功能的单链寡核苷酸分子，其序列可以通过体外筛选技术结合高通量测序快速鉴定获得，并可以通过固相合成实现大规模生产。本项目计划利用体外筛选技术分离靶向PD-1/PD-L1信号通路的非天然核酸TNA适配体，并评估此类适配体分子作为PD-1/PD-L1抑制剂对肿瘤生长的抑制作用。该类适配体不但具有可与抗体媲美的高亲和力和特异性，而且拥有比天然核酸更好的生物稳定性，同时在体内不具免疫原性。因此，靶向PD-1/PD-L1的非天然核酸适配体在肿瘤免疫治疗中拥有广阔的应用前景。

Tumor cells escape immunological surveillance by interacting with immune checkpoint proteins and inhibiting T cell activation. One of the key inhibitory immune signaling pathways involves the interaction of programmed death-1 (PD-1) protein and its ligand (PD-L1). PD-1:PD-L1 blockade using anti-PD-1 monoclonal antibodies such as nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) has proven to be an effective strategy to overcome immune evasion in patients with various cancers such as melanoma and non-small cell lung cancer. However, monoclonal antibody therapy inherently possesses some disadvantages including high manufacturing costs, long production cycle and immunogenicity with repeated administration. Aptamers are a new class of nucleic acid molecules capable of recognizing and binding a wide variety of targets with high affinity and specificity. Aptamers are identified rapidly by an in vitro selection and amplification process, and can be synthesized in a large scale by solid-phase synthesis. I hereby propose to isolate TNA, which is a type of unnatural nucleic acids, aptamers with affinity towards protein targets PD-1 and PD-L1. Compared with DNA and RNA, these TNA molecules contain unnatural backbones and exhibit intrinsic resistance to nuclease-mediated degradation. Importantly, these aptamers 1) exhibit strong affinity and high specificity, which is comparable to antibodies, towards their targets; 2) possess superior stability than natural nucleic acid counterparts in biological environment; 3) lack immunogenicity which often causes immune-related adverse events. Those aptamers with the ability to interfere with or block the PD-1:PD-L1 interaction would be studied further for their anti-tumor effects. Therefore, it is believed that the unnatural nucleic acid aptamers targeting PD-1/PD-L1 would have a promising prospect in future cancer immunotherapy.