HIF-1α和STAT3介导乏氧诱导的PD-L1上调在鼻咽癌免疫逃逸中的作用及机制研究

Nasopharyngeal carcinoma (NPC) is characterized by abundant vasculature but is also significantly presented with hypoxia. NPC nests are usually infiltrated by lymphocytes which are incapable of eliminating those cancer cells. Several studies have revealed that hypoxia might be an important mechanism leading to the formation of immune suppression microenvironment. Our preliminary study for the first time shows that hypoxia could induce the expression of Programed Death-ligand 1 (PD-L1), which is closely related to the level of Hypoxia-inducible Factor-1α (HIF-1α) and the activation of JAK2/STAT3. We therefore hypothesize that hypoxia could mediate the immune evasion of NPC via the up-regulation of PD-L1, which might be transcriptionally regulated by HIF-1α and STAT3. This project could deepen our understanding of immune evasion in NPC; reveal the new mechanism of drug-resistance mediated by hypoxia in NPC; and provide new theory and target for cancer prevention and treatment.

鼻咽癌是一个血管网丰富但乏氧明显的肿瘤，其癌巢中有大量的淋巴细胞浸润却难以发挥抗肿瘤免疫作用。既往研究表明乏氧可能是介导免疫抑制微环境形成的一个重要机制，我们在预实验中则首次发现鼻咽癌细胞中，乏氧可诱导程序性死亡配体1（PD-L1）的上调，并且PD-L1与乏氧诱导因子1α（HIF-1α）表达水平以及JAK2/STAT3通路的活化密切相关。我们还发现索拉非尼治疗后进展的鼻咽癌组织中，HIF-1α和PD-L1明显上调。因此我们假设，乏氧可能通过诱导HIF-1α及活化STAT3，从转录水平上调PD-L1，从而介导鼻咽癌免疫逃逸的发生。本课题将分别研究HIF-1α及STAT3介导乏氧下PD-L1上调的分子机制及其在鼻咽癌免疫逃逸中的作用。本研究将加深我们对鼻咽癌免疫逃逸机制的理解、揭示乏氧在鼻咽癌治疗耐药中的新机制，为肿瘤防治提供理论依据及新的靶点。

鼻咽癌是一个血管网丰富但乏氧明显的肿瘤，其癌巢中有大量淋巴细胞浸润却难以发挥抗肿瘤免疫作用。乏氧可能是介导免疫抑制微环境形成的一个重要机制。本研究在前期研究的基础上，探讨鼻咽癌患者肿瘤组织中HIF-1α、PD-L1表达水平及其与预后的关系；PD-L1在鼻咽癌细胞乏氧后上调及部分机制；乏氧激活前体药物TH-302在鼻咽癌中对缺氧肿瘤组织的杀伤作用。研究结果显示：1）鼻咽癌肿瘤组织中HIF-1α、PD-L1高表达的患者较低表达者预后较差。2）鼻咽癌细胞株在体外乏氧条件下，PD-L1 与HIF-1α的表达变化成正相关。3）乏氧激活前体药物TH-302在体外能有效的选择性杀伤乏氧肿瘤细胞，阻滞细胞周期于G2期，诱导细胞DNA双链断裂，抑制细胞内HIF-1α的表达；同时TH-302在体内外能够与DDP联合作用，抑制鼻咽癌肿瘤的生长，减少肿瘤组织内的缺氧区域。该研究进一步证实了肿瘤乏氧与肿瘤的免疫逃逸是密切相关的；乏氧激活前体药物TH-302在治疗乏氧肿瘤中具有一定的作用；揭示了乏氧在鼻咽癌治疗耐药中的部分机制，为肿瘤治疗提供了理论依据。