Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
J Immunother Cancer. 2022 Jun;10(6). doi: 10.1136/jitc-2022-004779.
Immune checkpoint inhibitors (ICIs) are promising agents for unresectable hepatocellular carcinoma (uHCC), but lack effective biomarker to predict outcomes. The gut microbiome can modulate tumor response to immunotherapy, but its effect on HCC remains unclear.
From May 2018 to February 2020, patients receiving ICI treatment for uHCC were prospectively enrolled; their fecal samples were collected before treatment. The fecal microbiota and metabolites were analyzed from 20 patients with radiology-proven objective responses (OR) and 21 randomly selected patients with progressive disease (PD). After March 2020, 33 consecutive Child-Pugh-A patients were recruited as a validation cohort. Additionally, feces from 17 healthy volunteers were collected for comparison of background microbes.
A significant dissimilarity was observed in fecal bacteria between patients with OR and patients with PD before immunotherapy. was enriched in patients with PD, whereas and were predominant in patients with OR. Ursodeoxycholic acid and ursocholic acid were significantly enriched in the feces of patients with OR and strongly correlated with the abundance of . The coexistence of enrichment and depletion significantly predicted better overall survival (OS). In the validation cohort, better progression-free survival (PFS) and OS were noted in patients who had a preferable microbial signature in comparison with counter-group (PFS: 8.8 months vs 1.8 months; OS: not reached vs 6.5 months, both p<0.001).
Fecal microbiota and bile acids were associated with outcomes of immunotherapy for uHCC. These findings highlight the potential role of gut microbiota and metabolites as biomarkers to predict outcomes of ICI-treated HCC.
免疫检查点抑制剂（ICIs）是治疗不可切除肝细胞癌（uHCC）的有前途的药物，但缺乏有效的生物标志物来预测疗效。肠道微生物群可以调节肿瘤对免疫治疗的反应，但它对 HCC 的影响尚不清楚。
本研究从 2018 年 5 月至 2020 年 2 月前瞻性地招募了接受 ICI 治疗 uHCC 的患者；在治疗前收集他们的粪便样本。从 20 名经影像学证实有客观反应（OR）的患者和 21 名随机选择的疾病进展（PD）患者中分析了粪便微生物群和代谢物。2020 年 3 月后，招募了 33 例连续的 Child-Pugh-A 患者作为验证队列。此外，收集了 17 名健康志愿者的粪便用于比较背景微生物。
在免疫治疗前，OR 患者和 PD 患者的粪便细菌存在显著差异。在 PD 患者中 富集，而 在 OR 患者中占优势。熊去氧胆酸和鹅去氧胆酸在 OR 患者的粪便中显著富集，与 的丰度呈强相关。 和 的富集共存和 的耗竭显著预测了更好的总生存期（OS）。在验证队列中，与对照组相比，具有更好微生物特征的患者具有更好的无进展生存期（PFS）和 OS（PFS：8.8 个月比 1.8 个月；OS：未达到比 6.5 个月，均 P<0.001）。
粪便微生物群和胆汁酸与 uHCC 的免疫治疗结果相关。这些发现强调了肠道微生物群和代谢物作为预测 ICI 治疗 HCC 疗效的生物标志物的潜力。
