Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine
Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine
复制标题
阻断AHR限制L-犬尿氨酸诱导的Treg-巨噬细胞抑制轴
DOI：
10.1038/s41467-020-17750-z
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发表时间：
2020-08-11
影响因子：
16.6
通讯作者：
Wolchok, Jedd D.
中科院分区：
文献类型：
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作者：
Campesato, Luis Felipe;Budhu, Sadna;Wolchok, Jedd D.
吲哚胺2，3-双加氧酶1和色氨酸2，3-双加氧酶2(IDO/TDO)的色氨酸分解代谢促进了不同癌症类型的免疫抑制。色氨酸代谢产物L-犬尿氨酸(Kyn)与配体激活的转录因子芳香烃受体(AHR)相互作用，促进T细胞和耐受性髓系细胞的产生，并上调CD8(+)T细胞中PD-1的表达。在这里，我们表明AHR通路在IDO/TDO过度表达的肿瘤中选择性地活跃，并与免疫检查点抑制剂的耐药性有关。我们证明IDO-Kyn-AHR介导的免疫抑制依赖于Tregs和肿瘤相关巨噬细胞之间的相互作用，这种相互作用可以被AHR抑制逆转。选择性AHR阻断可延缓IDO/TDO过表达肿瘤的进展，与PD-1阻断联合应用可提高其疗效。我们的发现表明，在表达IDO/TDO的肿瘤中阻断AHR通路将克服单一IDO或TDO靶向药物的限制，并构成一种个性化的免疫治疗方法，特别是与免疫检查点抑制剂联合使用。色氨酸代谢产物犬尿氨酸是芳香烃受体(AHR)的内源性配体。在这里，作者表明，在表达IDO/TDO的肿瘤中，AHR靶向抵消了调节性T细胞/巨噬细胞抑制轴，并与免疫检查点阻断协同作用，以阻止肿瘤生长。
Tryptophan catabolism by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2 (IDO/TDO) promotes immunosuppression across different cancer types. The tryptophan metabolite L-Kynurenine (Kyn) interacts with the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) to drive the generation of Tregs and tolerogenic myeloid cells and PD-1 up-regulation in CD8(+) T cells. Here, we show that the AHR pathway is selectively active in IDO/TDO-overexpressing tumors and is associated with resistance to immune checkpoint inhibitors. We demonstrate that IDO-Kyn-AHR-mediated immunosuppression depends on an interplay between Tregs and tumor-associated macrophages, which can be reversed by AHR inhibition. Selective AHR blockade delays progression in IDO/TDO-overexpressing tumors, and its efficacy is improved in combination with PD-1 blockade. Our findings suggest that blocking the AHR pathway in IDO/TDO expressing tumors would overcome the limitation of single IDO or TDO targeting agents and constitutes a personalized approach to immunotherapy, particularly in combination with immune checkpoint inhibitors. The tryptophan metabolite kynurenine is an endogenous ligand of the aryl hydrocarbon receptor (AHR). Here, the authors show that AHR targeting in IDO/TDO-expressing tumours counteracts a regulatory T cell/macrophage suppressive axis and synergizes with immune checkpoint blockade to hinder tumour growth.