Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment
Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment
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DOI：
10.1016/j.cell.2023.03.011
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发表时间：
2023-04-27
期刊：
影响因子：
64.5
通讯作者：
Meisel, Marlies
中科院分区：
文献类型：
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作者：
Bender, Mackenzie J.;McPherson, Alex C.;Meisel, Marlies
癌症患者使用益生菌的情况正在增加，包括那些接受免疫检查点抑制剂(ICI)治疗的患者。在这里，我们阐明了益生菌释放的芳烃受体(AhR)激动剂吲哚-3-醛(I3A)和肿瘤微环境中CD8T细胞之间的关键微生物-宿主串扰，它有效地增强了抗肿瘤免疫并促进了临床前黑色素瘤的ICI。我们的研究表明，益生菌reuri(LR)移位到黑色素瘤，在黑色素瘤中定居并持续存在，通过其释放的饮食色氨酸分解代谢产物I3A，局部促进产生干扰素-伽马的CD8 T细胞，从而支持ICI。此外，LR分泌的I3A既是启动抗肿瘤免疫的必要条件也是充分条件，CD8T细胞内AhR信号的缺失消除了LR的抗肿瘤作用。此外，富含色氨酸的饮食增强了LR和ICI诱导的抗肿瘤免疫，这依赖于CD8T细胞AhR信号。最后，我们为I3A在促进晚期黑色素瘤患者ICI疗效和生存率方面的潜在作用提供了证据。
The use of probiotics by cancer patients is increasing, including among those undergoing immune checkpoint inhibitor (ICI) treatment. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells within the tumor microenvironment that potently enhances antitumor immunity and facilitates ICI in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (Lr) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-gamma-producing CD8 T cells, thereby bolstering ICI. Moreover, Lr-secreted I3A was both necessary and sufficient to drive antitumor immunity, and loss of AhR signaling within CD8 T cells abrogated Lr's antitumor effects. Further, a tryptophan-enriched diet potentiated both Lr- and ICI-induced antitumor immunity, dependent on CD8 T cell AhR signaling. Finally, we provide evidence for a potential role of I3A in promoting ICI efficacy and survival in advanced melanoma patients.