加拿大多伦多大学Tracy L. McGaha研究组发现，色氨酸衍生的微生物代谢物激活肿瘤相关巨噬细胞中的芳香烃受体来抑制抗肿瘤免疫。这一研究成果发表在2022年2月8日出版的国际学术期刊《免疫》上。

研究人员揭示了芳烃受体（AhR）在胰腺导管腺癌（PDAC）中肿瘤相关巨噬细胞（TAM）功能的影响。TAM表现出高的AhR活性，Ahr缺陷的巨噬细胞发展出炎症表型。敲除骨髓细胞中的Ahr或对AhR进行药物抑制可减少PDAC的生长，提高免疫检查点阻断的效力，并增加肿瘤内IFNγ⁺ CD8⁺ T细胞的频率。这种效果不需要巨噬细胞色氨酸的代谢。

相反，巨噬细胞的AhR活性依赖于乳酸菌将饮食中的色氨酸代谢为吲哚。去除饮食中的色氨酸会降低TAM的AhR活性，并促进TNFα⁺ IFNγ⁺ CD8⁺ T细胞在肿瘤内的积累；提供饮食中的吲哚会阻止这种效果。在PDAC患者中，AHR的高表达与疾病的快速发展和死亡率有关，也与免疫抑制性TAM表型有关，这表明这一调节轴在人类疾病中得到保护。

据介绍，AhR是色氨酸代谢产物的传感器，也是免疫力的有效调节因子。

附：英文原文

Title: Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity

Author: Kebria Hezaveh, Rahul S. Shinde, Andreas Kltgen, Marie Jo Halaby, Sara Lamorte, M. Teresa Ciudad, Rene Quevedo, Luke Neufeld, Zhe Qi Liu, Robbie Jin, Barbara T. Grünwald, Elisabeth G. Foerster, Danica Chaharlangi, Mengdi Guo, Priya Makhijani, Xin Zhang, Trevor J. Pugh, Devanand M. Pinto, Ileana L. Co, Alison P. McGuigan, Gun Ho Jang, Rama Khokha, Pamela S. Ohashi, Grainne M. O’Kane, Steven Gallinger, William W. Navarre, Heather Maughan, Dana J. Philpott, David G. Brooks, Tracy L. McGaha

Issue&Volume: 2022/02/08

Abstract: The aryl hydrocarbon receptor (AhR) is a sensor of products of tryptophan metabolismand a potent modulator of immunity. Here, we examined the impact of AhR in tumor-associatedmacrophage (TAM) function in pancreatic ductal adenocarcinoma (PDAC). TAMs exhibitedhigh AhR activity and Ahr-deficient macrophages developed an inflammatory phenotype. Deletion of Ahr in myeloid cells or pharmacologic inhibition of AhR reduced PDAC growth, improvedefficacy of immune checkpoint blockade, and increased intra-tumoral frequencies ofIFNγ+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 reducedTAM 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 withan immune-suppressive TAM phenotype, suggesting conservation of this regulatory axisin human disease.

DOI: 10.1016/j.immuni.2022.01.006

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00035-8