Department of Liver Surgery, Peking Union Medical College Hospital, Beijing, China.
Department of Hepatobiliary Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
J Immunother Cancer. 2021 Dec;9(12). doi: 10.1136/jitc-2021-003334.
The gut microbiome is associated with the response to immunotherapy for different cancers. However, the impact of the gut microbiome on hepatobiliary cancers receiving immunotherapy remains unknown. This study aims to investigate the relationship between the gut microbiome and the clinical response to anti-programmed cell death protein 1 (PD-1) immunotherapy in patients with advanced hepatobiliary cancers.
Patients with unresectable hepatocellular carcinoma or advanced biliary tract cancers who have progressed from first-line chemotherapy (gemcitabine plus cisplatin) were enrolled. Fresh stool samples were collected before and during anti-PD-1 treatment and analyzed with metagenomic sequencing. Significantly differentially enriched taxa and prognosis associated taxa were identified. The Kyoto Encyclopedia of Genes and Genomes database and MetaCyc database were further applied to annotate the differentially enriched taxa to explore the potential mechanism of the gut microbiome influencing cancer immunotherapy.
In total, 65 patients with advanced hepatobiliary cancers receiving anti-PD-1 treatment were included in this study. Seventy-four taxa were significantly enriched in the clinical benefit response (CBR) group and 40 taxa were significantly enriched in the non-clinical benefit (NCB) group. Among these taxa, patients with higher abundance of Lachnospiraceae bacterium-GAM79 and Alistipes sp Marseille-P5997, which were significantly enriched in the CBR group, achieved longer progression-free survival (PFS) and overall survival (OS) than patients with lower abundance. Higher abundance of Ruminococcus calidus and Erysipelotichaceae bacterium-GAM147 enriched in the CBR group was also observed in patients with better PFS. In contrast, worse PFS and OS were found in patients with higher abundance of Veillonellaceae, which was significantly enriched in the NCB group. Functional annotation indicated that the taxa enriched in the CBR group were associated with energy metabolism while the taxa enriched in the NCB group were associated with amino acid metabolism, which may modulate the clinical response to immunotherapy in hepatobiliary cancers. In addition, immunotherapy-related adverse events were affected by the gut microbiome diversity and relative abundance.
We demonstrate that the gut microbiome is associated with the clinical response to anti-PD-1 immunotherapy in patients with hepatobiliary cancers. Taxonomic signatures enriched in responders are effective biomarkers to predict the clinical response and survival benefit of immunotherapy, which might provide a new therapeutic target to modulate the response to cancer immunotherapy.
肠道微生物群与不同癌症的免疫治疗反应有关。然而，肠道微生物群对接受免疫治疗的肝胆癌的影响尚不清楚。本研究旨在探讨肠道微生物群与晚期肝胆癌患者接受抗程序性细胞死亡蛋白 1（PD-1）免疫治疗的临床反应之间的关系。
纳入无法切除的肝细胞癌或一线化疗（吉西他滨加顺铂）进展后的晚期胆道癌患者。在接受抗 PD-1 治疗前和治疗期间采集新鲜粪便样本，并进行宏基因组测序分析。鉴定出显著差异富集的分类群和与预后相关的分类群。进一步应用京都基因与基因组百科全书数据库和 MetaCyc 数据库注释差异富集的分类群，以探讨肠道微生物群影响癌症免疫治疗的潜在机制。
本研究共纳入 65 例接受抗 PD-1 治疗的晚期肝胆癌患者。74 种分类群在临床获益反应（CBR）组中显著富集，40 种分类群在非临床获益（NCB）组中显著富集。在这些分类群中，Lachnospiraceae bacterium-GAM79 和 Alistipes sp Marseille-P5997 的丰度较高，这两种分类群在 CBR 组中显著富集，其无进展生存期（PFS）和总生存期（OS）长于丰度较低的患者。在 CBR 组中也观察到丰度较高的 Ruminococcus calidus 和 Erysipelotichaceae bacterium-GAM147 与更好的 PFS 相关。相反，在 NCB 组中丰度较高的 Veillonellaceae 与较差的 PFS 和 OS 相关。功能注释表明，CBR 组中富集的分类群与能量代谢有关，而 NCB 组中富集的分类群与氨基酸代谢有关，这可能调节肝胆癌的免疫治疗反应。此外，免疫治疗相关不良事件受肠道微生物多样性和相对丰度的影响。
我们证明肠道微生物群与肝胆癌患者接受抗 PD-1 免疫治疗的临床反应有关。在应答者中富集的分类群特征是预测免疫治疗临床反应和生存获益的有效生物标志物，这可能为调节癌症免疫治疗反应提供新的治疗靶点。
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