Dietary tryptophan metabolite released by intratumoral Lactobacillus reuterifacilitates immune checkpoint inhibitor treatment
Summary
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 Tcells 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-γ-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.
摘要
癌症患者使用益生菌的情况越来越多，包括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-甲醛（I3A）与肿瘤微环境中的CD8 T细胞之间的关键微生物-宿主串联，这种串联能有效地增强抗肿瘤免疫力，并促进临床前黑色素瘤的ICI治疗。我们的研究显示，益生菌雷特氏乳杆菌（Lr）会转移到黑色素瘤内，在黑色素瘤内定植并持续存在，通过其释放的饮食色氨酸分解物I3A，它在局部促进产生干扰素-γ的CD8 T细胞，从而增强ICI疗效。此外，Lr分泌的I3A是驱动抗肿瘤免疫的必要条件和充分条件，CD8 T细胞内AhR信号的缺失废除了Lr的抗肿瘤作用。此外，富含色氨酸的饮食能增强Lr和ICI诱导的抗肿瘤免疫力，这依赖于CD8 T细胞的AhR信号。最后，我们提供证据表明I3A在促进ICI疗效和晚期黑色素瘤患者生存方面的潜在作用。
参考文献
Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment. Cell. 2023 Apr 4:S0092-8674(23)00271-4. doi: 10.1016/j.cell. 2023.03.011. Epub ahead of print. PMID: 37028428.
