Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nat Commun. 2020 Aug 11;11(1):4011. doi: 10.1038/s41467-020-17750-z.
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.
色氨酸分解代谢酶吲哚胺 2,3-双加氧酶 1 和色氨酸 2,3-双加氧酶 2（IDO/TDO）促进了不同癌症类型的免疫抑制。色氨酸代谢产物 L-犬尿酸（Kyn）与配体激活转录因子芳香烃受体（AHR）相互作用，导致 Treg 和耐受原性髓样细胞的产生，并上调 CD8 T 细胞中的 PD-1。在这里，我们表明 AHR 途径在 IDO/TDO 过表达的肿瘤中是选择性激活的，并且与对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，AHR 抑制可以逆转这种相互作用。选择性 AHR 阻断延迟了 IDO/TDO 过表达肿瘤的进展，并且与 PD-1 阻断联合使用可提高其疗效。我们的研究结果表明，阻断 IDO/TDO 表达肿瘤中的 AHR 途径将克服单一 IDO 或 TDO 靶向药物的局限性，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时。
