Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment.

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2023-04-27 Epub Date: 2023-04-06 DOI:10.1016/j.cell.2023.03.011

Mackenzie J Bender, Alex C McPherson, Catherine M Phelps, Surya P Pandey, Colin R Laughlin, Jake H Shapira, Luzmariel Medina Sanchez, Mohit Rana, Tanner G Richie, Tahliyah S Mims, Angela M Gocher-Demske, Luisa Cervantes-Barragan, Steven J Mullett, Stacy L Gelhaus, Tullia C Bruno, Nikki Cannon, John A McCulloch, Dario A A Vignali, Reinhard Hinterleitner, Alok V Joglekar, Joseph F Pierre, Sonny T M Lee, Diwakar Davar, Hassane M Zarour, Marlies Meisel

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引用次数: 0

Abstract

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-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.

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瘤内乳杆菌释放的饮食色氨酸代谢物有助于免疫检查点抑制剂的治疗。

越来越多的癌症患者使用益生菌，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基烃受体（AhR）激动剂吲哚-3-甲醛（I3A）与肿瘤微环境中的CD8 T细胞之间关键的微生物-宿主串扰，这种串扰能有效增强抗肿瘤免疫力并促进临床前黑色素瘤的ICI治疗。我们的研究揭示了益生菌Lactobacillus reuteri（Lr）在黑色素瘤内的转运、定植和持续存在，通过其释放的饮食色氨酸代谢产物I3A，在局部促进产生干扰素-γ的CD8 T细胞，从而增强ICI。此外，Lr分泌的I3A对驱动抗肿瘤免疫既是必要的也是足够的，CD8 T细胞内AhR信号的缺失会削弱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，这取决于 CD8 T 细胞 AhR 信号转导。最后，我们为 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提供了证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.