Background: New strategies are needed to improve the response to immune checkpoint inhibitors for the treatment of hepatocellular carcinoma. Methods: Mice bearing HCC tumors were treated with PBS (control), a PD-1 antibody (PD-1Ab), proglumide, or the combination of proglumide and the PD-1Ab. The tumor microenvironment (TME) was evaluated histologically for fibrosis and by immunohistochemistry for immune cells. To investigate the mechanisms involved in T-cell efficiency, mouse spleen cells were isolated and examined for T-cell exhaustion markers and cytokine release. The mouse microbiome was analyzed using whole-genome sequencing before therapy and at the end of the study. Results: The combination of proglumide with a PD-1Ab decreased tumoral fibrosis better than monotherapy, and altered the immune cell signature in the TME by decreasing M2-polarized macrophages and increasing the influx of CD8+ T-cells. Proglumide monotherapy or in combination with the PD-1Ab decreased T-cell exhaustion markers and improved cytokine release. The combination therapy resulted in changes to the microbiome, including increased beneficial bacteria and genera known to enhance the efficacy of ICIs. Conclusions: Co-administration of proglumide with ICIs resulted in remodeling of the TME, changing a “cold” tumor to a “hot” immune-responsive tumor, activating T-cells, and altering the host microbiome to a population of bacteria that are beneficial.
背景：为改善肝细胞癌免疫检查点抑制剂治疗反应，需探索新策略。方法：对荷肝癌小鼠分别给予PBS（对照组）、PD-1抗体、丙谷胺或丙谷胺联合PD-1抗体治疗。通过组织学评估肿瘤微环境纤维化程度，并采用免疫组化分析免疫细胞浸润情况。为探究T细胞功能机制，分离小鼠脾细胞检测T细胞耗竭标志物及细胞因子释放水平。在治疗前和研究结束时通过全基因组测序分析小鼠肠道菌群。结果：丙谷胺联合PD-1抗体较单药治疗更能显著降低肿瘤纤维化程度，并通过减少M2型巨噬细胞极化、增加CD8+ T细胞浸润改变肿瘤微环境免疫特征。丙谷胺单药或联合治疗均可降低T细胞耗竭标志物表达并改善细胞因子释放。联合疗法引起肠道菌群改变，包括增加有益菌及已知能增强免疫检查点抑制剂疗效的菌属。结论：丙谷胺与免疫检查点抑制剂联用可重塑肿瘤微环境，将“冷肿瘤”转化为“热肿瘤”，激活T细胞功能，并将宿主菌群调整为有益菌群优势的生态结构。
肿瘤(癌症)患者之家