Deep learning model enables the discovery of a novel immunotherapeutic agent regulating the kynurenine pathway

Kynurenine (Kyn) is a key inducer of an immunosuppressive tumor microenvironment (TME). Although indoleamine 2,3-dioxygenase (IDO)-selective inhibitors have been developed to suppress the Kyn pathway, the results were not satisfactory due to the presence of various opposing mechanisms. Here, we empl...

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Autores principales:	Jeong Hun Kim, Won Suk Lee, Hye Jin Lee, Hannah Yang, Seung Joon Lee, so Jung Kong, Soyeon Je, Hyun-Jin Yang, Jongsun Jung, Jaekyung Cheon, Beodeul Kang, Hong Jae Chon, Chan Kim
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2021
Materias:	kynurenine pathway tumor microenvironment indoleamine 2 3-dioxygenase deep learning technology Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/b79d3c54e4ff44589373a0cee089c2d6
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spelling	oai:doaj.org-article:b79d3c54e4ff44589373a0cee089c2d62021-12-01T14:40:59ZDeep learning model enables the discovery of a novel immunotherapeutic agent regulating the kynurenine pathway2162-402X10.1080/2162402X.2021.2005280https://doaj.org/article/b79d3c54e4ff44589373a0cee089c2d62021-01-01T00:00:00Zhttp://dx.doi.org/10.1080/2162402X.2021.2005280https://doaj.org/toc/2162-402XKynurenine (Kyn) is a key inducer of an immunosuppressive tumor microenvironment (TME). Although indoleamine 2,3-dioxygenase (IDO)-selective inhibitors have been developed to suppress the Kyn pathway, the results were not satisfactory due to the presence of various opposing mechanisms. Here, we employed an orally administered novel Kyn pathway regulator to overcome the limitation of anti-tumor immune response. We identified a novel core structure that inhibited both IDO and TDO. An orally available lead compound, STB-C017 (designated hereafter as STB), effectively inhibited the enzymatic and cellular activity of IDO and TDO in vitro. Moreover, it potently suppressed Kyn levels in both the plasma and tumor in vivo. STB monotherapy increased the infiltration of CD8+ T cells into TME. In addition, STB reprogrammed the TME with widespread changes in immune-mediated gene signatures. Notably, STB-based combination immunotherapy elicited the most potent anti-tumor efficacy through concurrent treatment with immune checkpoint inhibitors, leading to complete tumor regression and long-term overall survival. Our study demonstrated that a novel Kyn pathway regulator derived using deep learning technology can activate T cell immunity and potentiate immune checkpoint blockade by overcoming an immunosuppressive TME.Jeong Hun KimWon Suk LeeHye Jin LeeHannah YangSeung Joon Leeso Jung KongSoyeon JeHyun-Jin YangJongsun JungJaekyung CheonBeodeul KangHong Jae ChonChan KimTaylor & Francis Grouparticlekynurenine pathwaytumor microenvironmentindoleamine 23-dioxygenasedeep learning technologyImmunologic diseases. AllergyRC581-607Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENOncoImmunology, Vol 10, Iss 1 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	kynurenine pathway tumor microenvironment indoleamine 2 3-dioxygenase deep learning technology Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	kynurenine pathway tumor microenvironment indoleamine 2 3-dioxygenase deep learning technology Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Jeong Hun Kim Won Suk Lee Hye Jin Lee Hannah Yang Seung Joon Lee so Jung Kong Soyeon Je Hyun-Jin Yang Jongsun Jung Jaekyung Cheon Beodeul Kang Hong Jae Chon Chan Kim Deep learning model enables the discovery of a novel immunotherapeutic agent regulating the kynurenine pathway
description	Kynurenine (Kyn) is a key inducer of an immunosuppressive tumor microenvironment (TME). Although indoleamine 2,3-dioxygenase (IDO)-selective inhibitors have been developed to suppress the Kyn pathway, the results were not satisfactory due to the presence of various opposing mechanisms. Here, we employed an orally administered novel Kyn pathway regulator to overcome the limitation of anti-tumor immune response. We identified a novel core structure that inhibited both IDO and TDO. An orally available lead compound, STB-C017 (designated hereafter as STB), effectively inhibited the enzymatic and cellular activity of IDO and TDO in vitro. Moreover, it potently suppressed Kyn levels in both the plasma and tumor in vivo. STB monotherapy increased the infiltration of CD8+ T cells into TME. In addition, STB reprogrammed the TME with widespread changes in immune-mediated gene signatures. Notably, STB-based combination immunotherapy elicited the most potent anti-tumor efficacy through concurrent treatment with immune checkpoint inhibitors, leading to complete tumor regression and long-term overall survival. Our study demonstrated that a novel Kyn pathway regulator derived using deep learning technology can activate T cell immunity and potentiate immune checkpoint blockade by overcoming an immunosuppressive TME.
format	article
author	Jeong Hun Kim Won Suk Lee Hye Jin Lee Hannah Yang Seung Joon Lee so Jung Kong Soyeon Je Hyun-Jin Yang Jongsun Jung Jaekyung Cheon Beodeul Kang Hong Jae Chon Chan Kim
author_facet	Jeong Hun Kim Won Suk Lee Hye Jin Lee Hannah Yang Seung Joon Lee so Jung Kong Soyeon Je Hyun-Jin Yang Jongsun Jung Jaekyung Cheon Beodeul Kang Hong Jae Chon Chan Kim
author_sort	Jeong Hun Kim
title	Deep learning model enables the discovery of a novel immunotherapeutic agent regulating the kynurenine pathway
title_short	Deep learning model enables the discovery of a novel immunotherapeutic agent regulating the kynurenine pathway
title_full	Deep learning model enables the discovery of a novel immunotherapeutic agent regulating the kynurenine pathway
title_fullStr	Deep learning model enables the discovery of a novel immunotherapeutic agent regulating the kynurenine pathway
title_full_unstemmed	Deep learning model enables the discovery of a novel immunotherapeutic agent regulating the kynurenine pathway
title_sort	deep learning model enables the discovery of a novel immunotherapeutic agent regulating the kynurenine pathway
publisher	Taylor & Francis Group
publishDate	2021
url	https://doaj.org/article/b79d3c54e4ff44589373a0cee089c2d6
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Deep learning model enables the discovery of a novel immunotherapeutic agent regulating the kynurenine pathway

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