Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine

Abstract

Tryptophan catabolism by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3dioxygenase 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/TDOoverexpressing 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.

Metabolic Cancer-Macrophage Crosstalk in the Tumor Microenvironment

“…Kynurenine is a metabolite produced in the major metabolism pathway of Trp, which can be catalyzed by three enzymes: indoleamine 2,3-dioxygenase 1 (IDO1), IDO2 or tryptophan-2,3-dioxygenase (TDO). Multiple human cancer types such as brain and colon cancer secrete kynurenine into the TME [44,77], affecting macrophages in a paracrine manner ( Figure 2) [78]. Kynurenine can signal through GPR35, which is highly expressed on macrophages [79].…”

“…Increased IDO and TDO expression in human melanoma is associated with an elevated abundance of TAMs with increased CD206 expression and decreased expression of Nos2 (the gene encoding iNOS), Il12, Tnf, Cd86 and Cd40. These TAMs also upregulate the kynurenine receptor aryl hydrocarbon receptor (AHR), inhibit CD8 + cytotoxic functions and engage in a pro-tumoral cooperation with Tregs [78]. Furthermore, blockade of AHR signaling enhances anti-programmed cell death protein 1 (αPD-1) therapy effects in a myeloid-dependent manner in a B16 melanoma model [78].…”

“…These TAMs also upregulate the kynurenine receptor aryl hydrocarbon receptor (AHR), inhibit CD8 + cytotoxic functions and engage in a pro-tumoral cooperation with Tregs [78]. Furthermore, blockade of AHR signaling enhances anti-programmed cell death protein 1 (αPD-1) therapy effects in a myeloid-dependent manner in a B16 melanoma model [78]. Additionally, kynurenine-activated AHR signaling was found to elevate C-C chemokine receptor type 2 (CCR2) expression, leading to monocyte recruitment and increased tumor growth in vivo [80].…”

“…Reversing (metabolic) polarization towards pro-tumoral TAMs or re-educating TAMs to gain anti-tumor responses could decrease metastasis and enhance immune effector functions [37,41,65,66,78,86,116]. Oncometabolites can induce cancer-promoting signaling pathways in macrophages, including PI3K signaling via the protein kinase B (PKB/AKT) and mTOR pathways.…”

“…Tryptophan metabolism constitutes a promising metabolic target in general, as IDO/TDO inhibitors may decrease tumor kynurenine production while simultaneously providing tryptophan to T cells in the TME, enabling them to carry out anti-tumor responses [125,126]. Decreased kynurenine levels or AHR blockade may additionally counteract pro-tumoral TAM polarization and improve αPD-1 therapy response [78,125,126]. However, although promising in earlier clinical trials, in a phase III trial with an IDO inhibitor, the latter effect could not be replicated in metastatic melanoma patients [127].…”