Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma

PURPOSE: Glioblastoma (GBM) is an incurable primary brain tumor that has not benefited from immunotherapy to date. More than 90% of GBM expresses the tryptophan (Trp) metabolic enzyme, indoleamine 2,3-dioxygenase 1 (IDO). This observation supported the historical hypothesis that IDO suppresses the a...

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Autores principales: Zhai, Lijie, Bell, April, Ladomersky, Erik, Lauing, Kristen L., Bollu, Lakshmi, Nguyen, Brenda, Genet, Matthew, Kim, Miri, Chen, Peiwen, Mi, Xinlei, Wu, Jennifer D., Schipma, Matthew J., Wray, Brian, Griffiths, John, Unwin, Richard D., Clark, Simon J., Acharya, Rajesh, Bao, Riyue, Horbinski, Craig, Lukas, Rimas V., Schiltz, Gary E., Wainwright, Derek A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639612/
https://www.ncbi.nlm.nih.gov/pubmed/34479957
http://dx.doi.org/10.1158/1078-0432.CCR-21-1392
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author Zhai, Lijie
Bell, April
Ladomersky, Erik
Lauing, Kristen L.
Bollu, Lakshmi
Nguyen, Brenda
Genet, Matthew
Kim, Miri
Chen, Peiwen
Mi, Xinlei
Wu, Jennifer D.
Schipma, Matthew J.
Wray, Brian
Griffiths, John
Unwin, Richard D.
Clark, Simon J.
Acharya, Rajesh
Bao, Riyue
Horbinski, Craig
Lukas, Rimas V.
Schiltz, Gary E.
Wainwright, Derek A.
author_facet Zhai, Lijie
Bell, April
Ladomersky, Erik
Lauing, Kristen L.
Bollu, Lakshmi
Nguyen, Brenda
Genet, Matthew
Kim, Miri
Chen, Peiwen
Mi, Xinlei
Wu, Jennifer D.
Schipma, Matthew J.
Wray, Brian
Griffiths, John
Unwin, Richard D.
Clark, Simon J.
Acharya, Rajesh
Bao, Riyue
Horbinski, Craig
Lukas, Rimas V.
Schiltz, Gary E.
Wainwright, Derek A.
author_sort Zhai, Lijie
collection PubMed
description PURPOSE: Glioblastoma (GBM) is an incurable primary brain tumor that has not benefited from immunotherapy to date. More than 90% of GBM expresses the tryptophan (Trp) metabolic enzyme, indoleamine 2,3-dioxygenase 1 (IDO). This observation supported the historical hypothesis that IDO suppresses the antitumor immune response solely through a mechanism that requires intratumoral Trp depletion. However, recent findings led us to investigate the alternative hypothesis that IDO suppresses the anti-GBM immune response independent of its association with Trp metabolism. EXPERIMENTAL DESIGN: IDO-deficient GBM cell lines reconstituted with IDO wild-type or IDO enzyme–null cDNA were created and validated in vitro and in vivo. Microarray analysis was conducted to search for genes that IDO regulates, followed by the analysis of human GBM cell lines, patient GBM and plasma, and The Cancer Genome Atlas (TCGA) database. Ex vivo cell coculture assays, syngeneic and humanized mouse GBM models, were used to test the alternative hypothesis. RESULTS: Nonenzymic tumor cell IDO activity decreased the survival of experimental animals and increased the expression of complement factor H (CFH) and its isoform, factor H like protein 1 (FHL-1) in human GBM. Tumor cell IDO increased CFH and FHL-1 expression independent of Trp metabolism. Increased intratumoral CFH and FHL-1 levels were associated with poorer survival among patients with glioma. Similar to IDO effects, GBM cell FHL-1 expression increased intratumoral regulatory T cells (Treg) and myeloid-derived suppressor cells while it decreased overall survival in mice with GBM. CONCLUSIONS: Our study reveals a nonmetabolic IDO-mediated enhancement of CFH expression and provides a new therapeutic target for patients with GBM.
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spelling pubmed-86396122021-12-03 Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma Zhai, Lijie Bell, April Ladomersky, Erik Lauing, Kristen L. Bollu, Lakshmi Nguyen, Brenda Genet, Matthew Kim, Miri Chen, Peiwen Mi, Xinlei Wu, Jennifer D. Schipma, Matthew J. Wray, Brian Griffiths, John Unwin, Richard D. Clark, Simon J. Acharya, Rajesh Bao, Riyue Horbinski, Craig Lukas, Rimas V. Schiltz, Gary E. Wainwright, Derek A. Clin Cancer Res Translational Cancer Mechanisms and Therapy PURPOSE: Glioblastoma (GBM) is an incurable primary brain tumor that has not benefited from immunotherapy to date. More than 90% of GBM expresses the tryptophan (Trp) metabolic enzyme, indoleamine 2,3-dioxygenase 1 (IDO). This observation supported the historical hypothesis that IDO suppresses the antitumor immune response solely through a mechanism that requires intratumoral Trp depletion. However, recent findings led us to investigate the alternative hypothesis that IDO suppresses the anti-GBM immune response independent of its association with Trp metabolism. EXPERIMENTAL DESIGN: IDO-deficient GBM cell lines reconstituted with IDO wild-type or IDO enzyme–null cDNA were created and validated in vitro and in vivo. Microarray analysis was conducted to search for genes that IDO regulates, followed by the analysis of human GBM cell lines, patient GBM and plasma, and The Cancer Genome Atlas (TCGA) database. Ex vivo cell coculture assays, syngeneic and humanized mouse GBM models, were used to test the alternative hypothesis. RESULTS: Nonenzymic tumor cell IDO activity decreased the survival of experimental animals and increased the expression of complement factor H (CFH) and its isoform, factor H like protein 1 (FHL-1) in human GBM. Tumor cell IDO increased CFH and FHL-1 expression independent of Trp metabolism. Increased intratumoral CFH and FHL-1 levels were associated with poorer survival among patients with glioma. Similar to IDO effects, GBM cell FHL-1 expression increased intratumoral regulatory T cells (Treg) and myeloid-derived suppressor cells while it decreased overall survival in mice with GBM. CONCLUSIONS: Our study reveals a nonmetabolic IDO-mediated enhancement of CFH expression and provides a new therapeutic target for patients with GBM. American Association for Cancer Research 2021-12-01 2021-09-03 /pmc/articles/PMC8639612/ /pubmed/34479957 http://dx.doi.org/10.1158/1078-0432.CCR-21-1392 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Translational Cancer Mechanisms and Therapy
Zhai, Lijie
Bell, April
Ladomersky, Erik
Lauing, Kristen L.
Bollu, Lakshmi
Nguyen, Brenda
Genet, Matthew
Kim, Miri
Chen, Peiwen
Mi, Xinlei
Wu, Jennifer D.
Schipma, Matthew J.
Wray, Brian
Griffiths, John
Unwin, Richard D.
Clark, Simon J.
Acharya, Rajesh
Bao, Riyue
Horbinski, Craig
Lukas, Rimas V.
Schiltz, Gary E.
Wainwright, Derek A.
Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma
title Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma
title_full Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma
title_fullStr Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma
title_full_unstemmed Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma
title_short Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma
title_sort tumor cell ido enhances immune suppression and decreases survival independent of tryptophan metabolism in glioblastoma
topic Translational Cancer Mechanisms and Therapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639612/
https://www.ncbi.nlm.nih.gov/pubmed/34479957
http://dx.doi.org/10.1158/1078-0432.CCR-21-1392
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