Department of Medicine III, School of Medicine, Technical University of Munich, Munich, Germany; Centre for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.
EBioMedicine. 2023 Nov;97:104834. doi: 10.1016/j.ebiom.2023.104834. Epub 2023 Oct 20.
Inter-individual differences in response to immune checkpoint inhibitors (ICI) remain a major challenge in cancer treatment. The composition of the gut microbiome has been associated with differential ICI outcome, but the underlying molecular mechanisms remain unclear, and therapeutic modulation challenging.
We established an in vivo model to treat C57Bl/6j mice with the type-I interferon (IFN-I)-modulating, bacterial-derived metabolite desaminotyrosine (DAT) to improve ICI therapy. Broad spectrum antibiotics were used to mimic gut microbial dysbiosis and associated ICI resistance. We utilized genetic mouse models to address the role of host IFN-I in DAT-modulated antitumour immunity. Changes in gut microbiota were assessed using 16S-rRNA sequencing analyses.
We found that oral supplementation of mice with the microbial metabolite DAT delays tumour growth and promotes ICI immunotherapy with anti-CTLA-4 or anti-PD-1. DAT-enhanced antitumour immunity was associated with more activated T cells and natural killer cells in the tumour microenvironment and was dependent on host IFN-I signalling. Consistent with this, DAT potently enhanced expansion of antigen-specific T cells following vaccination with an IFN-I-inducing adjuvant. DAT supplementation in mice compensated for the negative effects of broad-spectrum antibiotic-induced dysbiosis on anti-CTLA-4-mediated antitumour immunity. Oral administration of DAT altered the gut microbial composition in mice with increased abundance of bacterial taxa that are associated with beneficial response to ICI immunotherapy.
We introduce the therapeutic use of an IFN-I-modulating bacterial-derived metabolite to overcome resistance to ICI. This approach is a promising strategy particularly for patients with a history of broad-spectrum antibiotic use and associated loss of gut microbial diversity.
Melanoma Research Alliance, Deutsche Forschungsgemeinschaft, German Cancer Aid, Wilhelm Sander Foundation, Novartis Foundation.
个体对免疫检查点抑制剂（ICI）的反应存在差异，这仍然是癌症治疗的主要挑战。肠道微生物组的组成与 ICI 结果的差异有关，但潜在的分子机制尚不清楚，治疗调节也具有挑战性。
我们建立了一个体内模型，用细菌衍生的代谢物脱氨酶酪氨酸（DAT）治疗 C57Bl/6j 小鼠，以改善 ICI 治疗。广谱抗生素用于模拟肠道微生物失调和相关的 ICI 耐药性。我们利用遗传小鼠模型来解决宿主 IFN-I 在 DAT 调节抗肿瘤免疫中的作用。使用 16S-rRNA 测序分析评估肠道微生物群的变化。
我们发现，给小鼠口服补充微生物代谢物 DAT 可延迟肿瘤生长并促进抗 CTLA-4 或抗 PD-1 的 ICI 免疫治疗。DAT 增强的抗肿瘤免疫与肿瘤微环境中更活跃的 T 细胞和自然杀伤细胞有关，并且依赖于宿主 IFN-I 信号。与此一致的是，DAT 可在使用 IFN-I 诱导佐剂接种疫苗后强力增强抗原特异性 T 细胞的扩增。DAT 补充在广谱抗生素诱导的失调对抗 CTLA-4 介导的抗肿瘤免疫产生负面影响的情况下补偿了小鼠的作用。DAT 在小鼠中的口服给药改变了肠道微生物组成，增加了与 ICI 免疫治疗有益反应相关的细菌分类群的丰度。
我们引入了一种 IFN-I 调节的细菌衍生代谢物的治疗用途，以克服对 ICI 的耐药性。这种方法是一种很有前途的策略，特别是对于有广谱抗生素使用史和相关肠道微生物多样性丧失的患者。
黑色素瘤研究联盟、德国研究基金会、德国癌症援助协会、威廉桑德基金会、诺华基金会。
