旨在研究肠道微生物组与不可切除的肝细胞癌 (HCC) 中基于抗 PD-1 的联合疗法的反应之间的关系。我们的目的是确定潜在的非侵入性生物标志物和调节 HCC 免疫治疗的新策略。在这项研究中，从美国癌症医院接受基于抗 PD-1 的联合治疗的不可切除 HCC 患者收集了新鲜粪便样本和临床数据。 2020年1月至2021年12月期间，中国医学科学院进行了一项研究。根据患者对治疗的反应将患者分为两组：治疗有反应组（R组）和治疗无反应组（NR组）。采用全基因组鸟枪策略对肠道微生物组的组成和多样性进行生物信息分析，包括分类组成分析、Alpha多样性分析、Beta多样性分析和差异富集细菌类群分析。根据线性判别分析效应大小 (LEfSe) 的大小，确定了 R 组和 NR 组之间差异富集的细菌分类群，并分析了它们对患者生存的影响。总共 45 名符合条件的不可切除 HCC 患者接受了抗-R 组和 NR 组的治疗。基于PD-1的联合疗法参与了这项研究。 R组和NR组患者的肠道微生物组成和Alpha多样性没有统计学差异，但Beta多样性有统计学差异。 （PERMANOVA 测试，P = 0.006）。基于LEfSe分析，我们进一步鉴定了R组中的56个富集细菌类群和NR组中的44个富集细菌类群（LDA>2.66，P<0.05）。与丰度较低的患者相比，柯林斯菌属、Ruminococcus_AM4211 和 Ruminococcus_AF25_28AC 丰度较高的患者的中位 PFS 和中位 OS 较长（P < 0.05）。相反，Bacteroides_AF20_13LB 和 Veillonella_atypica 高丰度患者的中位 PFS 和 OS 显着短于低丰度患者（P < 0.05）。多变量分析显示，Bacteroides_AF20_13LB和Ruminococcus_AF25_28AC的丰度是PFS的独立相关因素，Bacteroides_AF20_13LB的丰度是OS的独立相关因素。特定肠道菌群的富集影响抗肿瘤药物治疗HCC的临床疗效和生存获益。 PD-1 疗法可能是一种有前景的非侵入性肠道微生物生物标志物，也是调节 HCC 免疫治疗的新策略。版权所有 © 2024 Xin、Peng、Song、Zhou、Huang 和 Cao。

To investigate the relationship between the gut microbiome and the response to anti-PD-1-based combination therapy in unresectable hepatocellular carcinoma (HCC). We aimed to identify potential non-invasive biomarkers and new strategies to modulate immunotherapy in HCC.In this study, fresh stool samples and clinical data were collected from unresectable HCC patients treated with anti-PD-1-based combination therapy at the Cancer Hospital of the Chinese Academy of Medical Sciences between January 2020 and December 2021. The patients were divided into two groups based on their response to treatment: the treatment responder group (R group) and the treatment non-responder group (NR group). The composition and diversity of the gut microbiome were bioinformatically analyzed by using the Whole Genome Shotgun strategy, including taxonomic composition analysis, Alpha diversity analysis, Beta diversity analysis, and differentially enriched bacterial taxa analysis. Differentially enriched bacterial taxa between R and NR groups were identified based on the magnitude of the linear discriminant analysis effect size (LEfSe) and analyzed for their impact on the survival of the patient.A total of 45 eligible patients with unresectable HCC treated with anti-PD-1-based combination therapy participated in this study. The gut microbiological composition and Alpha diversity of patients were not statistically different, but there was a statistically significant difference in Beta diversity between the R and NR groups. (PERMANOVA tests, P = 0.006). We further identified 56 enriched bacterial taxa in the R group and 44 enriched bacterial taxa in the NR group based on the LEfSe analysis (LDA >2.66, P< 0.05). Patients with a high abundance of Collinsella genus, Ruminococcus_AM4211, and Ruminococcus_AF25_28AC had a longer median PFS and median OS compared to those with low abundance (P < 0.05). On the contrary, the median PFS and OS of patients with a high abundance of Bacteroides_AF20_13LB and Veillonella_atypica were significantly shorter than those of patients with low abundance (P < 0.05). The multivariate analysis showed that the abundance of Bacteroides_AF20_13LB and Ruminococcus_ AF25_28AC was independent related factors for PFS, and the abundance of Bacteroides_AF20_13LB was an independent related factor of OS.The enrichment of specific gut microbiota affected clinical efficacy and survival benefits in HCC treated with anti-PD-1 therapy and may be a promising non-invasive gut microbial biomarker and a new strategy for modulating immunotherapy in HCC.Copyright © 2024 Xin, Peng, Song, Zhou, Huang and Cao.