法尼酯X受体FXR介导NSCLC免疫治疗的增效作用研究

Anti-PD-1/PD-L1immunotherapy has been a hot topic for the treatment of advanced non-small cell lung cancer (NSCLC). However, there are significant limitations in clinical practice. Our previous study found that there was a significant negative correlation between farnesoid X receptor (FXR) and PD-L1 expression in NSCLC tissue samples. In vitro experiments revealed that FXR down-regulation promoted the expression of PD-L1 in NSCLC cells, while FXR over-expression reduced PD-L1 expression. This research will be conducted from the perspectives of the regulatory effects of FXR on tumor immune response to clarify the role of FXR in regulating PD-L1 expression in the tumor immunotherapy. We will further validate that the animals with decreased expression of FXR enhanced the PD-L1 antibody response rate by up-regulating the expression of PD-L in lung cancer tissues, thereby achieving the goal of inhibiting tumor growth. Meanwhile, we will use co-culture system, gene interference or over-expression technologies in vivo and in vitro as well as clinical correlation research to investigate the influence of FXR on immune response, related immune cells and inflammatory cytokins and their molecular modulation mechanisms in NSCLC. This study will help reveal the synergistic effect of targeted FXR against tumor immunotherapy, to optimize and enrich the optimal population suitable for anti-PD-1/PD-L1 immunotherapy, and to clarify the regulating effects of FXR on NSCLC immune reaction and their mechanisms.

抗PD-1/PD-L1免疫治疗已成晚期非小细胞肺癌（NSCLC）治疗的热点，但目前在临床实践中存在很大的局限性。我们前期研究发现NSCLC组织样本中法尼酯X受体FXR与PD-L1表达存在明显负相关，体外抑制FXR可上调NSCLC中PD-L1表达，而过表达 FXR 则下调 PD-L1的表达。本课题从FXR调控肿瘤免疫反应的功能视角出发，体内验证FXR低表达动物通过上调PD-L1表达，而引起的对PD-L1抗体反应率增强、肿瘤生长受抑的效应；同时采用肿瘤细胞与免疫细胞共培养体系、干扰或过表达手段结合临床样本，考察FXR在肿瘤免疫微环境中对肿瘤细胞和免疫细胞功能表型的调控作用，进一步明确FXR调控PD-L1表达对抗肿瘤免疫治疗的作用，并探讨具体的分子机制。本研究有助于优化和拓宽PD-1/PD-L1免疫治疗的最佳受益人群。

免疫治疗目前已成晚期非小细胞肺癌（NSCLC）治疗的热点，但在临床实践中存在很大的局限性，因此如何拓展免疫治疗人群成为目前的研究难点。我们的研究聚焦于胆汁酸受体在调控肿瘤免疫中的作用，我们发现胆汁酸核受体FXR与PDL1表达呈负相关，而且FXR可以在转录水平实现对PDL1的调控，我们进一步探索了肿瘤中FXR的高表达对肿瘤免疫的影响，我们发现FXR的过表达可以抑制CD8+T细胞的活化，参与构建了免疫抑制微环境，在FXR高表达可以增敏PD1的治疗效果，为临床中PD1的精准治疗提供理论依据，此外我们也探索了胆汁酸膜受体TGR5在肿瘤相关巨噬细胞中的作用，我们发现在肿瘤微环境中，TGR5-/- BMDM中促瘤M2表型减弱，而具有抗肿瘤作用的M1表型增强，吞噬肿瘤能力增强，TGR5-/- BMDM可以显著抑制肿瘤生长，重塑肿瘤微环境提高抗肿瘤免疫。我们的研究从肿瘤微环境与肿瘤互动调控的动态视角出发，阐明了TGR5在肿瘤微环境中作用，TGR5通过调控TAM抑制抗肿瘤免疫反应促进肺癌进展。我们的研究有助于全面理解胆汁酸受体参与肺癌进程的作用特性，有望揭示基于微环境免疫特征的新型免疫治疗靶点。