Metabolomic adaptations and correlates of survival to immune checkpoint blockade

Li, Haoxin; Bullock, Kevin; Gurjao, Carino; Braun, David A.; Shukla, Sachet A.; Bossé, Dominick; Lalani, Aly-Khan A.; Gopal, Shuba; Jin, Chelsea; Horak, Christine E.; Wind‐Rotolo, Megan; Signoretti, Sabina; McDermott, David F.; Freeman, Gordon J.; Allen, Eliezer M. Van; Schreiber, Stuart L.; Hodi, F. Stephen; Sellers, William R.; Garraway, Levi A.; Clish, Clary B.; Choueiri, Toni K.; Giannakis, Marios

doi:10.1038/s41467-019-12361-9

Cited by 162 publications

(149 citation statements)

References 21 publications

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“…Given the mouting evidence that high IDO expression can lead to inhibition of the effector function of T cells, either directly or indirectly through non-T cell components 36,37 , strategies to effectively target this metabolic pathway can reverse tumor immune resistance mechanisms. Interestingly, increases in the IDO/TDO-product Kyn in the serum of patients receiving anti-PD-1 were recently reported as an adaptive resistance mechanism associated with worse overall survival 13,38 . Similarly, we here found that upregulation of Kyndegrading enzymes correlates with good response to anti-PD-1 therapy (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Immunomonitoring of blood samples can highlight such dynamic shifts in ongoing immune responses. In NSCLC, RCC and melanoma patients the baseline value of systemic Kyn/Trp as well as its dynamics during treatment course were associated with patient outcome (189,193). In this way the Kyn/Trp ratio could be a marker best capturing IDO activity at a specific moment and perhaps could have relevance in therapeutic monitoring.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study profiling Kyn/Trp in more than 900 human cancer cell lines demonstrated that secreted Kyn can be attributed to both IDO and TDO expression by tumor cells (195). However, another study observed a correlation of the Kyn/Trp ratio with PD-L1 and IDO but not with TDO mRNA levels in melanoma samples after 4 cycles of anti-PD-1 immunotherapy (193). Nevertheless, the authors argued that additional sources of Trp to Kyn degradation outside the tumor may exist.…”

Section: Ido In the Peripheral Bloodmentioning

confidence: 99%

IDO Expression in Cancer: Different Compartment, Different Functionality?

2020

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Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic haem-containing enzyme involved in the degradation of tryptophan to kynurenine. Although initially thought to be solely implicated in the modulation of innate immune responses during infection, subsequent discoveries demonstrated IDO1 as a mechanism of acquired immune tolerance. In cancer, IDO1 expression/activity has been observed in tumor cells as well as in the tumor-surrounding stroma, which is composed of endothelial cells, immune cells, fibroblasts, and mesenchymal cells. IDO1 expression/activity has also been reported in the peripheral blood. This manuscript reviews available data on IDO1 expression, mechanisms of its induction, and its function in cancer for each of these compartments. In-depth study of the biological function of IDO1 according to the expressing (tumor) cell can help to understand if and when IDO1 inhibition can play a role in cancer therapy.

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“…55,56 At last, profiling of advanced melanoma and renal cell carcinoma (RCC) patients showed that Kyn/Trp alterations correlated with overall survival upon administration of nivolumab (a PD-1 blocker). 57 Thus, IDO inhibition stands out as a promising strategy to (re)instance cancer immunosurveillance. Indeed, IDO inhibitors demonstrated their ability to successfully cooperate with immunotherapy, radiotherapy or chemotherapy even in tumors that are normally resistant to conventional treatments.…”

Section: Introductionmentioning

confidence: 99%

Trial watch: IDO inhibitors in cancer therapy

et al. 2020

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Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first, rate-limiting step of the so-called "kynurenine pathway", which converts the essential amino acid L-tryptophan (Trp) into the immunosuppressive metabolite L-kynurenine (Kyn). While expressed constitutively by some tissues, IDO1 can also be induced in specific subsets of antigen-presenting cells that ultimately favor the establishment of immune tolerance to tumor antigens. At least in part, the immunomodulatory functions of IDO1 can be explained by depletion of Trp and accumulation of Kyn and its derivatives. In animal tumor models, genetic or pharmacological IDO1 inhibition can cause the (re)activation of anticancer immune responses. Similarly, neoplasms expressing high levels of IDO1 may elude anticancer immunosurveillance. Therefore, IDO1 inhibitors represent promising therapeutic candidates for cancer therapy, and some of them have already entered clinical evaluation. Here, we summarize preclinical and clinical studies testing IDO1-targeting interventions for oncologic indications.

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Metabolomic adaptations and correlates of survival to immune checkpoint blockade

Cited by 162 publications

References 21 publications

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

IDO Expression in Cancer: Different Compartment, Different Functionality?

Trial watch: IDO inhibitors in cancer therapy

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