Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao, China.
Thorac Cancer. 2024 May;15(14):1149-1163. doi: 10.1111/1759-7714.15303. Epub 2024 Apr 4.
BACKGROUND: Immunotherapy has revolutionized cancer treatment. Recent studies have suggested that the efficacy of immunotherapy can be further enhanced by the influence of gut microbiota. In this study, we aimed to investigate the impact of bacteria on the effectiveness of cancer immunotherapy by combining analysis of clinical samples with validation in animal models. METHODS: In order to characterize the diversity and composition of microbiota and its relationship with response to immune checkpoint inhibitors (ICIs), 16S ribosomal RNA (rRNA) and GC-MS sequencing was performed on 71 stool samples from patients with advanced non-small cell lung cancer (NSCLC) prior to treatment with immune checkpoint blockade (ICB). Furthermore, fecal microbiota transplantation (FMT) was performed from different patients into mice and a subcutaneous tumor model established using the Lewis lung cancer cell line to evaluate the therapeutic effect of PD-1 on mice with varying gut microbiota. RESULTS: The results demonstrated a significant association between elevated gut microbiota diversity and response to treatment with ICIs, p < 0.05. Faecalibacterium was markedly increased in the gut microbiota of responders (R), accompanied by increased short-chain fatty acid (SCFA) levels, especially butanoic acid, acetic acid and hexanoic acid, p < 0.05. Additionally, FMT from R and nonresponders (NR) could promote an anticancer effect and reduce the expression of Ki-67 cells in tumors in mice, p < 0.05. Moreover, R and NR FMT did not alter PD-L1 expression in the tumor tissues of mice, p > 0.05. The diversity of gut microbiota consistently correlated with an optimistic prognosis in NSCLC patients with immunotherapy, which could be functionally mediated by SCFAs. CONCLUSION: The findings of the present study indicated that the diversity of gut microbiota and SCFAs is related to the efficacy of immunotherapy. FMT can effectively delay tumor progression, and enhance the effect of immunotherapy, thus providing evidence for improving the efficacy of immunotherapy in NSCLC patients.
背景：免疫疗法已经彻底改变了癌症的治疗方式。最近的研究表明，肠道微生物群的影响可以进一步增强免疫疗法的疗效。在这项研究中，我们旨在通过结合临床样本分析和动物模型验证，研究细菌对癌症免疫疗法疗效的影响。
方法：为了描述微生物群的多样性和组成及其与免疫检查点抑制剂（ICIs）反应的关系，在开始免疫检查点阻断（ICB）治疗之前，对 71 名晚期非小细胞肺癌（NSCLC）患者的粪便样本进行了 16S 核糖体 RNA（rRNA）和 GC-MS 测序。此外，从不同患者中进行粪便微生物群移植（FMT），并将其移植到小鼠中，使用 Lewis 肺癌细胞系建立皮下肿瘤模型，以评估不同肠道微生物群的 PD-1 对小鼠的治疗效果。
结果：结果表明，肠道微生物群多样性与对 ICI 治疗的反应之间存在显著关联，p<0.05。应答者（R）的肠道微生物群中粪杆菌明显增加，同时短链脂肪酸（SCFA）水平升高，尤其是丁酸、乙酸和己酸，p<0.05。此外，来自 R 和无应答者（NR）的 FMT 可促进抗肿瘤作用，并降低小鼠肿瘤中 Ki-67 细胞的表达，p<0.05。此外，R 和 NR FMT 并未改变小鼠肿瘤组织中 PD-L1 的表达，p>0.05。免疫治疗的 NSCLC 患者肠道微生物群的多样性与乐观的预后一致，这可能是由 SCFAs 介导的。
结论：本研究结果表明，肠道微生物群的多样性和 SCFAs 与免疫治疗的疗效有关。FMT 可有效延缓肿瘤进展，增强免疫治疗效果，为提高 NSCLC 患者免疫治疗疗效提供依据。
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