膀胱癌通过乳酸流重编码肿瘤相关巨噬细胞的机制研究

Bladder cancer is the most common urinary system tumor which progress fast and is resistant to chemotherapy and radiotherapy. One of the major reasons for its progression and drug-tolerance is that it can re-program tumor associated macrophages (TAMs) in the tumor microenvironment to cause immunotolerance. The study of the mechanisms of the reprogramming of TAMs may help us to find new targets for bladder treatment. Bladder cancer mainly relies on aerobic glycolysis for energy. This metabolism pattern produces ATP as well as lactate at a fast rate. In our previous studies, we found that lactate could induce the polarization of M2 macrophage, and more importantly, blocking lactate shuttle could significantly inhibit the reprogramming of TAMs by bladder cancer cells, which suggests that bladder cancer derived lactate shuttle may be an important pathway of inducing immunotolerance. According to the result of the literature search and our previous study, we find that MCT4/LDH/HIF1 may be the mechanism of this phenomenon. In the present study, we will systematically elucidate role of lactate shuttle in the bladder cancer derived reprogramming of TAMs, and study the effect of MCT4/LDH/HIF1 pathway on this process, in order to find new targets for bladder immunotherapy.

膀胱癌是我国最常见的泌尿系统肿瘤，进展迅速，放化疗疗效差。其快速进展并产生耐药性的一个重要原因是其可以重新编码肿瘤微环境内的肿瘤相关巨噬细胞等免疫细胞，造成肿瘤免疫耐受。寻找肿瘤细胞重编码肿瘤相关巨噬细胞的机制可能为膀胱癌的治疗提供新的思路。膀胱癌能量代谢方式主要为有氧糖酵解，可快速释放能量并产生大量乳酸。我们的前期实验发现乳酸可诱导肿瘤相关巨噬细胞分化为M2型巨噬细胞，并且阻断乳酸的跨膜转运可显著抑制膀胱癌细胞对肿瘤相关巨噬细胞的重编码。提示乳酸流可能是膀胱癌细胞诱导免疫耐受的重要途径，根据文献检索及预实验我们认为MCT4/LDHB/HIF1α通路可能为该现象的主要机制。在本项目中我们将采用微流控芯片、shRNA阻断等技术系统分析乳酸流在膀胱癌重编码肿瘤相关巨噬细胞中的作用，并进一步研究MCT4/LDHB/HIF1α通路在这一过程中的作用，以期为膀胱癌的免疫治疗提供新的靶点。

膀胱癌是我国最常见的泌尿系统肿瘤，进展迅速，放化疗疗效差。其快速进展并产生耐药性的一个重要原因是其可以重新编码肿瘤微环境内的肿瘤相关巨噬细胞等免疫细胞，造成肿瘤免疫耐受。寻找肿瘤细胞重编码肿瘤相关巨噬细胞的机制可能为膀胱癌的治疗提供新的思路。膀胱癌能量代谢方式主要为有氧糖酵解，可快速释放能量并产生大量乳酸。我们通过shRNA阻断、WesterBlot、免疫组化等实验在2D共培养、微流控共培养模型及裸鼠成瘤模型中证实了膀胱癌可通过乳酸流及MCT4/LDHB/HIF1α通路诱导M2型肿瘤相关巨噬细胞的产生，阻断该通路上的相关蛋白可抑制膀胱癌细胞的活率及迁移能力。本研究发现乳酸流是膀胱肿瘤治疗的潜在治疗靶点。