Doneparthi Priyanka S, Cao Hong, Chen Wenqiang, Dou Wenyu, Fang Hong-Bin, Smith Jill P
Department of Oncology, Georgetown University, Washington, DC 20007, USA.
Department of Medicine, Georgetown University, Washington, DC 20007, USA.
Cancers (Basel). 2025 Sep 14;17(18):2998. doi: 10.3390/cancers17182998.
New strategies are needed to improve the response to immune checkpoint inhibitors for the treatment of hepatocellular carcinoma.
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.
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.
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.
需要新的策略来改善免疫检查点抑制剂治疗肝细胞癌的反应。
用PBS（对照）、PD-1抗体（PD-1Ab）、丙谷胺或丙谷胺与PD-1Ab的组合治疗携带肝癌肿瘤的小鼠。通过组织学评估肿瘤微环境（TME）的纤维化情况，并通过免疫组织化学评估免疫细胞。为了研究T细胞效率所涉及的机制，分离小鼠脾细胞并检测T细胞耗竭标志物和细胞因子释放。在治疗前和研究结束时使用全基因组测序分析小鼠微生物组。
丙谷胺与PD-1Ab联合使用比单一疗法能更好地减少肿瘤纤维化，并通过减少M2极化巨噬细胞和增加CD8+ T细胞的流入来改变TME中的免疫细胞特征。丙谷胺单一疗法或与PD-1Ab联合使用可降低T细胞耗竭标志物并改善细胞因子释放。联合治疗导致微生物组发生变化，包括有益细菌增加以及已知可增强免疫检查点抑制剂疗效的菌属增加。
丙谷胺与免疫检查点抑制剂联合使用导致TME重塑，将“冷”肿瘤转变为“热”免疫反应性肿瘤，激活T细胞，并将宿主微生物组改变为有益细菌群体。
