Indoleamine 2, 3-Dioxygenase Promotes Aryl Hydrocarbon Receptor-Dependent Differentiation Of Regulatory B Cells in Lung Cancer

Regulatory B cells (Breg) are IL-10 producing subsets of B cells that contribute to immunosuppression in the tumor microenvironment (TME). Breg are elevated in patients with lung cancer; however, the mechanisms underlying Breg development and their function in lung cancer have not been adequately el...

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Autores principales:	Sultan Tousif, Yong Wang, Joshua Jackson, Kenneth P. Hough, John G. Strenkowski, Mohammad Athar, Victor J. Thannickal, Robert H. McCusker, Selvarangan Ponnazhagan, Jessy S. Deshane
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	IDO L-Kynurenine Breg cells MDSC (myeloid-derived suppressor cells) TME (tumor microenvironment) immunosuppression Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/1942612f213d4139803771b8c0d5424a
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spelling	oai:doaj.org-article:1942612f213d4139803771b8c0d5424a2021-11-19T07:53:45ZIndoleamine 2, 3-Dioxygenase Promotes Aryl Hydrocarbon Receptor-Dependent Differentiation Of Regulatory B Cells in Lung Cancer1664-322410.3389/fimmu.2021.747780https://doaj.org/article/1942612f213d4139803771b8c0d5424a2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.747780/fullhttps://doaj.org/toc/1664-3224Regulatory B cells (Breg) are IL-10 producing subsets of B cells that contribute to immunosuppression in the tumor microenvironment (TME). Breg are elevated in patients with lung cancer; however, the mechanisms underlying Breg development and their function in lung cancer have not been adequately elucidated. Herein, we report a novel role for Indoleamine 2, 3- dioxygenase (IDO), a metabolic enzyme that degrades tryptophan (Trp) and the Trp metabolite L-kynurenine (L-Kyn) in the regulation of Breg differentiation in the lung TME. Using a syngeneic mouse model of lung cancer, we report that Breg frequencies significantly increased during tumor progression in the lung TME and secondary lymphoid organs, while Breg were reduced in tumor-bearing IDO deficient mice (IDO-/-). Trp metabolite L-Kyn promoted Breg differentiation in-vitro in an aryl hydrocarbon receptor (AhR), toll-like receptor-4-myeloid differentiation primary response 88, (TLR4-MyD88) dependent manner. Importantly, using mouse models with conditional deletion of IDO in myeloid-lineage cells, we identified a significant role for immunosuppressive myeloid-derived suppressor cell (MDSC)-associated IDO in modulating in-vivo and ex-vivo differentiation of Breg. Our studies thus identify Trp metabolism as a therapeutic target to modulate regulatory B cell function during lung cancer progression.Sultan TousifYong WangJoshua JacksonKenneth P. HoughJohn G. StrenkowskiMohammad AtharVictor J. ThannickalRobert H. McCuskerSelvarangan PonnazhaganJessy S. DeshaneFrontiers Media S.A.articleIDOL-KynurenineBreg cellsMDSC (myeloid-derived suppressor cells)TME (tumor microenvironment)immunosuppressionImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	IDO L-Kynurenine Breg cells MDSC (myeloid-derived suppressor cells) TME (tumor microenvironment) immunosuppression Immunologic diseases. Allergy RC581-607
spellingShingle	IDO L-Kynurenine Breg cells MDSC (myeloid-derived suppressor cells) TME (tumor microenvironment) immunosuppression Immunologic diseases. Allergy RC581-607 Sultan Tousif Yong Wang Joshua Jackson Kenneth P. Hough John G. Strenkowski Mohammad Athar Victor J. Thannickal Robert H. McCusker Selvarangan Ponnazhagan Jessy S. Deshane Indoleamine 2, 3-Dioxygenase Promotes Aryl Hydrocarbon Receptor-Dependent Differentiation Of Regulatory B Cells in Lung Cancer
description	Regulatory B cells (Breg) are IL-10 producing subsets of B cells that contribute to immunosuppression in the tumor microenvironment (TME). Breg are elevated in patients with lung cancer; however, the mechanisms underlying Breg development and their function in lung cancer have not been adequately elucidated. Herein, we report a novel role for Indoleamine 2, 3- dioxygenase (IDO), a metabolic enzyme that degrades tryptophan (Trp) and the Trp metabolite L-kynurenine (L-Kyn) in the regulation of Breg differentiation in the lung TME. Using a syngeneic mouse model of lung cancer, we report that Breg frequencies significantly increased during tumor progression in the lung TME and secondary lymphoid organs, while Breg were reduced in tumor-bearing IDO deficient mice (IDO-/-). Trp metabolite L-Kyn promoted Breg differentiation in-vitro in an aryl hydrocarbon receptor (AhR), toll-like receptor-4-myeloid differentiation primary response 88, (TLR4-MyD88) dependent manner. Importantly, using mouse models with conditional deletion of IDO in myeloid-lineage cells, we identified a significant role for immunosuppressive myeloid-derived suppressor cell (MDSC)-associated IDO in modulating in-vivo and ex-vivo differentiation of Breg. Our studies thus identify Trp metabolism as a therapeutic target to modulate regulatory B cell function during lung cancer progression.
format	article
author	Sultan Tousif Yong Wang Joshua Jackson Kenneth P. Hough John G. Strenkowski Mohammad Athar Victor J. Thannickal Robert H. McCusker Selvarangan Ponnazhagan Jessy S. Deshane
author_facet	Sultan Tousif Yong Wang Joshua Jackson Kenneth P. Hough John G. Strenkowski Mohammad Athar Victor J. Thannickal Robert H. McCusker Selvarangan Ponnazhagan Jessy S. Deshane
author_sort	Sultan Tousif
title	Indoleamine 2, 3-Dioxygenase Promotes Aryl Hydrocarbon Receptor-Dependent Differentiation Of Regulatory B Cells in Lung Cancer
title_short	Indoleamine 2, 3-Dioxygenase Promotes Aryl Hydrocarbon Receptor-Dependent Differentiation Of Regulatory B Cells in Lung Cancer
title_full	Indoleamine 2, 3-Dioxygenase Promotes Aryl Hydrocarbon Receptor-Dependent Differentiation Of Regulatory B Cells in Lung Cancer
title_fullStr	Indoleamine 2, 3-Dioxygenase Promotes Aryl Hydrocarbon Receptor-Dependent Differentiation Of Regulatory B Cells in Lung Cancer
title_full_unstemmed	Indoleamine 2, 3-Dioxygenase Promotes Aryl Hydrocarbon Receptor-Dependent Differentiation Of Regulatory B Cells in Lung Cancer
title_sort	indoleamine 2, 3-dioxygenase promotes aryl hydrocarbon receptor-dependent differentiation of regulatory b cells in lung cancer
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/1942612f213d4139803771b8c0d5424a
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Indoleamine 2, 3-Dioxygenase Promotes Aryl Hydrocarbon Receptor-Dependent Differentiation Of Regulatory B Cells in Lung Cancer

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