LXR-α/CCR7介导的前列腺癌免疫逃逸及其机制研究

CCR7 plays an important role in dendritic cell homing, and deficient of CCR7 fails to induce anti-cancer immune response in vivo. In our previous study, it was discovered that prostate cancer cells could have an effect on dendritic cells, including activation of LXR-α and improved expression of its target gene ABCG1, decreased expression of NF-κB-p65 in nucleus and IκB-α phosphoryltion in cytoplasm, as well as inhibition of CCR7 expression on cell surface, which demonstrated that prostate cancer could escape immune surveillance or immune response via hindering dendritic cell homing by LXR-α/NF-κB/CCR7 routing. This study is proposed to systematically explore the role of LXR-α/NF-κB/CCR7 routing in prostate cancer immune escape in vitro cell experiment and in vivo animal study respectively by usage of molecular biological technique, which would enrich the knowledge of mechanism in prostate cancer immune escape and supply a new idea and theory for finding effective immunotherapy and appropriate molecular target drug.

CCR7是树突状细胞归巢的最关键分子，缺乏CCR7的DCs在体内难以启动肿瘤免疫应答。前期工作中，课题组发现前列腺癌细胞可使树突状细胞内LXR-α活化及促进其靶基因ABCG1转录和表达，下调细胞核中NF-κB-p65表达水平及细胞浆中磷酸化IκB-α表达水平，抑制细胞表面CCR7水平，提示前列腺癌可能通过LXR-α/NF-κB/CCR7途径阻碍树突状细胞归巢来逃逸免疫监控或免疫应答。本研究拟通过分子生物学实验方法分别在体外细胞实验和体内动物水平系统探讨LXR-α/NF-κB/CCR7通路在前列腺癌免疫逃逸中的作用，为丰富前列腺癌免疫逃逸机制以及临床上寻找有效的前列腺癌免疫治疗方法或合适的药物干预靶分子提供新思路和实验依据。

前列腺癌是老年男性最常见的恶性肿瘤之一，免疫逃逸是其进展的一个重要机制。DCs在肿瘤免疫应答中起关键作用，它能在外周组织中捕获肿瘤相关抗原，然后归巢至引流淋巴节，活化T细胞，启动抗肿瘤免疫反应。CCR7是DCs归巢的最关键分子，缺乏CCR7的DCs在体内难以启动肿瘤免疫应答。因此，本研究通过分子生物学实验方法分别在体外细胞实验和体内动物水平探讨了小鼠前列腺癌细胞RM-1逃逸免疫应答的可能机制。结果显示RM-1细胞的培养上清液能使小鼠骨髓来源DCs的LXR­α活化，通过下调细胞核中NF-κB-p65表达水平及细胞浆中磷酸化IκB-α表达水平来抑制DCs细胞表面CCR7水平，降低DCs趋化能力，使DCs归巢至引流淋巴结能力受损，刺激T细胞能力减弱。通过抑制RM-1细胞LXR­α配体产生来阻断DCs的LXR­α活化可促进RM-1移植瘤内的CD11c+CCR7+DCs及T细胞侵润，减缓肿瘤的生长速率和延长小鼠的生存时间。本研究揭示了前列腺癌免疫逃逸的新机制，为研究有效的前列腺癌免疫治疗方法或寻找合适的药物干预靶分子提供新思路和实验依据。