肠道菌群调控胰腺癌Th1免疫应答作用及机制研究

Pancreatic cancer is the most lethal common cancer, whose initiation and progression are believed closely associated with immunosurveillance. Recent researches revealed that gut microbiota played an important role in shaping systemic immune response and affected the therapeutic activities of chemotherapeutic and immunotherapeutic interventions. However, little is known about its role in the context of pancreatic cancer currently. Our previous studies found that the gut microbiota structure and composition of mice were altered after orthotopic transplantation of mouse pancreatic cancer. Furthermore, restoring gut microbiota with fecal transplantation could inhibit tumor growth, increase type 1 helper T cells (Th1) ratio in tumor infiltrating T cells, elevate interferon-γ (IFN-γ) level in circulation and enhance myeloid differentiation factor 88 (MYD88) pathway activation in gut. Besides, MYD88 knockout mice showed faster tumor growth, decreased Th1 ratio in tumor infiltrating T cells and lower IFN-γ level in circulation compared with wild-type mice. In this project, we will make clear the effect of gut microbiota on Th1 immune response and tumor growth in the context of pancreatic cancer and clarify the role of MYD88 pathway in this process in a mouse model of allograft orthotopic pancreatic cancer transplantation. Then, we will screen and identify the key bacteria within gut microbiota that regulate Th1 immune response and tumor growth by pyrosequencing of 16S ribosomal RNA gene. Finally, we will explore the possibility of improving the efficacy of immunotherapy in pancreatic cancer by manipulating gut microbiota. The results will provide novel strategies for pancreatic cancer treatment and enrich the gut microbiota-tumor immunity theory.

胰腺癌是恶性程度极高的常见肿瘤，其发生发展与免疫监视联系密切。近年研究发现肠道菌群可调控机体免疫应答，影响肿瘤化疗及免疫治疗效果。但目前肠道菌群在胰腺癌中的作用知之甚少。我们前期研究发现，小鼠接受胰腺癌原位移植瘤后肠道菌群原有结构与组成遭到破坏；通过粪便移植修复原有菌群可减缓肿瘤生长，上调肿瘤浸润T细胞中辅助性T细胞1（Th1）比例与机体γ-干扰素水平，激活肠道MYD88通路；此外，MYD88敲除小鼠胰腺癌生长加快，肿瘤浸润T细胞中Th1比例与机体γ-干扰素水平下降。本课题拟在前期研究基础上，通过小鼠同种异体原位移植瘤模型明确肠道菌群对Th1免疫应答及胰腺癌生长的影响，并阐明MYD88通路在其中的作用；利用16S核糖体RNA测序技术鉴定肠道中关键调控菌群，并探索操纵肠道菌群改善胰腺癌免疫治疗效果的可行性。研究结果将为改善胰腺癌治疗效果提供新的思路，并进一步丰富“肠道菌群-肿瘤免疫”理论。

胰腺癌预后极差，免疫治疗效果不佳，肠道微生态可能在胰腺癌发生发展及免疫治疗中发挥重要作用。本项目通过培育自发胰腺癌基因工程小鼠，构建免疫正常小鼠同种异体原位种植瘤模型，探究肠道微生态与胰腺癌的双相调控作用，分析胰腺癌发生发展过程中肿瘤免疫微环境的动态变化，并探索胰腺癌免疫治疗优化策略。此外，本项目建设基于真实世界数据的胰腺癌专病科研数据库，推动胰腺癌临床与基础研究协同发展。研究结果表明，胰腺癌的发生发展导致小鼠肠道微生态失衡，清除肠道菌群和重建肠道微生态可调控小鼠胰腺癌发展。研究系统描绘了小鼠胰腺癌动态免疫图谱，并找到改善胰腺癌免疫治疗效果的潜在靶点。实验证实，联合抗PD-L1治疗可逆转小鼠胰腺癌免疫抑制的肿瘤微环境，抑制甚至清除肿瘤，延长个体生存。研究结果将为改善胰腺癌治疗效果提供新策略，并进一步丰富“肠道菌群-肿瘤免疫”理论。