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

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Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment
Cell ( IF 45.5 ) Pub Date : 2023-04-06 , DOI: 10.1016/j.cell.2023.03.011
Mackenzie J Bender ₁ , Alex C McPherson ₂ , Catherine M Phelps ₃ , Surya P Pandey ₁ , Colin R Laughlin ₁ , Jake H Shapira ₁ , Luzmariel Medina Sanchez ₃ , Mohit Rana ₁ , Tanner G Richie ₄ , Tahliyah S Mims ₅ , Angela M Gocher-Demske ₆ , Luisa Cervantes-Barragan ₇ , Steven J Mullett ₈ , Stacy L Gelhaus ₈ , Tullia C Bruno ₉ , Nikki Cannon ₁₀ , John A McCulloch ₁₀ , Dario A A Vignali ₉ , Reinhard Hinterleitner ₁₁ , Alok V Joglekar ₁₂ , Joseph F Pierre ₅ , Sonny T M Lee ₄ , Diwakar Davar ₁₃ , Hassane M Zarour ₁₄ , Marlies Meisel ₁₁

Affiliation

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Graduate Program of Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Division of Biology, Kansas State University, Manhattan, KS, USA.
Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA.
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.

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.

中文翻译：

瘤内罗伊氏乳杆菌释放的膳食色氨酸代谢物促进免疫检查点抑制剂治疗

癌症患者对益生菌的使用正在增加，包括接受免疫检查点抑制剂 (ICI) 治疗的患者。在这里，我们阐明了肿瘤微环境中益生菌释放的芳烃受体 (AhR) 激动剂吲哚-3-醛 (I3A) 和 CD8 T 细胞之间的关键微生物-宿主串扰，该串扰可有效增强抗肿瘤免疫并促进临床前黑色素瘤中的 ICI。我们的研究表明，益生菌罗伊氏乳杆菌( Lr ) 易位、定植并在黑色素瘤内持续存在，通过其释放的膳食色氨酸分解代谢物 I3A，它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 对于驱动抗肿瘤免疫来说是必要且充分的，CD8 T 细胞内 AhR 信号传导的丧失消除了Lr的抗肿瘤作用。此外，富含色氨酸的饮食可增强Lr和 ICI 诱导的抗肿瘤免疫，这取决于 CD8 T 细胞 AhR 信号传导。最后，我们提供了 I3A 在促进晚期黑色素瘤患者 ICI 疗效和生存方面的潜在作用的证据。

更新日期：2023-04-06

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