Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity.
Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity.
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DOI：
10.1016/j.immuni.2022.01.006
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发表时间：
2022-02-08
期刊：
影响因子：
32.4
通讯作者：
McGaha TL
中科院分区：
文献类型：
--
作者：
Hezaveh K;Shinde RS;Klötgen A;Halaby MJ;Lamorte S;Ciudad MT;Quevedo R;Neufeld L;Liu ZQ;Jin R;Grünwald BT;Foerster EG;Chaharlangi D;Guo M;Makhijani P;Zhang X;Pugh TJ;Pinto DM;Co IL;McGuigan AP;Jang GH;Khokha R;Ohashi PS;O'Kane GM;Gallinger S;Navarre WW;Maughan H;Philpott DJ;Brooks DG;McGaha TL
芳香烃受体(AhR)是色氨酸代谢产物的感受器，是一种强大的免疫调节剂。在这里，我们研究了AhR对胰腺导管腺癌肿瘤相关巨噬细胞()功能的影响。TAMS表现出高的AhR活性，AhR缺乏的巨噬细胞出现炎症表型。髓系细胞中AhR的缺失或对AhR的药物抑制减少了PDAC的生长，提高了免疫检查点阻断的效果，并增加了干扰素γ+CD8+T细胞在肿瘤内的频率。这种作用不需要巨噬细胞的色氨酸代谢。相反，巨噬细胞AhR的活性依赖于乳杆菌将饮食中的色氨酸代谢成吲哚。去除饮食中的色氨酸降低了的AhR活性，并促进了肿瘤坏死因子α+干扰素γ+CD8+T细胞在肿瘤内的积聚；提供饮食吲哚可阻断这一作用。在PDAC患者中，AHR的高表达与疾病的快速进展和死亡率以及免疫抑制的表型有关，这表明这一调节轴在人类疾病中是保守的。AHR引导巨噬细胞极化。Hezaveh等人。确认AhR在胰腺癌的肿瘤巨噬细胞功能中起关键作用，AhR抑制炎性T细胞的浸润并促进生长。肠道微生物组产生的色氨酸代谢产物激活了AHR，人类疾病显示巨噬细胞AHR的表达与不良预后相关。
The aryl hydrocarbon receptor (AhR) is a sensor of products of tryptophan metabolism and a potent modulator of immunity. Here, we examined the impact of AhR in tumor-associated macrophage (TAM) function in pancreatic ductal adenocarcinoma (PDAC). TAMs exhibited high AhR activity and Ahr-deficient macrophages developed an inflammatory phenotype. Deletion of Ahr in myeloid cells or pharmacologic inhibition of AhR reduced PDAC growth, improved efficacy of immune checkpoint blockade, and increased intra-tumoral frequencies of IFNγ+CD8+ T cells. Macrophage tryptophan metabolism was not required for this effect. Rather, macrophage AhR activity was dependent on Lactobacillus metabolization of dietary tryptophan to indoles. Removal of dietary tryptophan reduced TAM AhR activity and promoted intra-tumoral accumulation of TNFα+IFNγ+CD8+ T cells; provision of dietary indoles blocked this effect. In patients with PDAC, high AHR expression associated with rapid disease progression and mortality, as well as with an immune-suppressive TAM phenotype, suggesting conservation of this regulatory axis in human disease. AhR directs macrophage polarization. Hezaveh et al. identified a key role for AhR in tumor macrophage function in pancreatic cancer, with AhR suppressing inflammatory T cell infiltration and promoting growth. AhR was activated by gut microbiome-produced tryptophan metabolites and human disease showed association of macrophage AHR expression and worse outcomes.
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影响因子：
4.6
作者：
Hubbard TD;Murray IA;Bisson WH;Lahoti TS;Gowda K;Amin SG;Patterson AD;Perdew GH
通讯作者：
Perdew GH
影响因子：
24.8
作者：
Halaby, Marie Jo;Hezaveh, Kebria;McGaha, Tracy L.
通讯作者：
McGaha, Tracy L.
DOI：
10.1084/jem.20151193
发表时间：
2016-10-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Afik R;Zigmond E;Vugman M;Klepfish M;Shimshoni E;Pasmanik-Chor M;Shenoy A;Bassat E;Halpern Z;Geiger T;Sagi I;Varol C
通讯作者：
Varol C
影响因子：
--
作者：
Franchini, Anthony M;Myers, Jason R;Lawrence, B Paige
通讯作者：
Lawrence, B Paige
影响因子：
46.9
作者：
Butler A;Hoffman P;Smibert P;Papalexi E;Satija R
通讯作者：
Satija R