Hepatocellular Carcinoma Cells Are Protected From Immunolysis by Mesenchymal Stromal Cells Through Indoleamine 2,3 Dioxygenase

B7 family proteins serve as checkpoint molecules that protect tumors from T cell mediated lysis. Tryptophan degrading enzymes indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3 dioxygenase (TDO) also induce T cell immune tolerance. However, little is known about the relative contribution of B7 mol...

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Autores principales:	Raghavan Chinnadurai, Amanda Paige Porter, Mihir Patel, Ariel Joy Lipat, Mathews H. Forsberg, Devi Rajan, Peiman Hematti, Christian M. Capitini, Charles Bruker
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	mesenchymal stromal cells indoleamine 2,3 dioxygenase (IDO) hepatocellular carcinoma B7 family checkpoints immunotherapy Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/99ee81a0e482403ab182d77d66ad8b4a
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spelling	oai:doaj.org-article:99ee81a0e482403ab182d77d66ad8b4a2021-11-12T06:22:04ZHepatocellular Carcinoma Cells Are Protected From Immunolysis by Mesenchymal Stromal Cells Through Indoleamine 2,3 Dioxygenase2296-634X10.3389/fcell.2021.715905https://doaj.org/article/99ee81a0e482403ab182d77d66ad8b4a2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.715905/fullhttps://doaj.org/toc/2296-634XB7 family proteins serve as checkpoint molecules that protect tumors from T cell mediated lysis. Tryptophan degrading enzymes indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3 dioxygenase (TDO) also induce T cell immune tolerance. However, little is known about the relative contribution of B7 molecules, tryptophan degrading enzymes, as well as the impact of tumor and stromal cell interactions to the development of immunosuppressive tumor microenvironment. To investigate such interactions, we used a tripartite model of human hepatocellular carcinoma cell line (HepG2) and mesenchymal stromal cells (MSCs) co-cultured with peripheral blood mononuclear cells (PBMCs). Co-culture of HepG2 cells and activated PBMCs demonstrate that HepG2 cells undergo PBMC mediated cytolysis, despite constitutive expression of B7-H3 and upregulation of PD-L1 by IFNγ. Knockdown of B7-H3, PD-L1 or IDO does not modulate PBMC mediated lysis of HepG2 cells. However, TNFα preactivation enhances lysis of HepG2 cells, and blocking of TNFα production from PBMCs protects HepG2 cells. On the other hand, MSCs protect HepG2 cells from PBMC mediated lysis, even in the presence of TNFα. Further investigation showed that MSC mediated protection is associated with the unique secretome profile of upregulated and downregulated cytokines and chemokines. IFNγ activated MSCs are superior to TNFα activated or control MSCs in protecting HepG2 cells. Blockade of IFNγ driven IDO activity completely abolishes the ability of MSCs to protect HepG2 cells from cytolysis by PBMCs. These results suggest that inhibition of IFNγ activation of IDO induction in stromal cells, combined with usage of TNFα, could be a novel immunotherapeutic strategy to induce regression of hepatocellular carcinoma.Raghavan ChinnaduraiAmanda Paige PorterMihir PatelAriel Joy LipatMathews H. ForsbergDevi RajanPeiman HemattiChristian M. CapitiniCharles BrukerFrontiers Media S.A.articlemesenchymal stromal cellsindoleamine 2,3 dioxygenase (IDO)hepatocellular carcinomaB7 family checkpointsimmunotherapyBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	mesenchymal stromal cells indoleamine 2,3 dioxygenase (IDO) hepatocellular carcinoma B7 family checkpoints immunotherapy Biology (General) QH301-705.5
spellingShingle	mesenchymal stromal cells indoleamine 2,3 dioxygenase (IDO) hepatocellular carcinoma B7 family checkpoints immunotherapy Biology (General) QH301-705.5 Raghavan Chinnadurai Amanda Paige Porter Mihir Patel Ariel Joy Lipat Mathews H. Forsberg Devi Rajan Peiman Hematti Christian M. Capitini Charles Bruker Hepatocellular Carcinoma Cells Are Protected From Immunolysis by Mesenchymal Stromal Cells Through Indoleamine 2,3 Dioxygenase
description	B7 family proteins serve as checkpoint molecules that protect tumors from T cell mediated lysis. Tryptophan degrading enzymes indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3 dioxygenase (TDO) also induce T cell immune tolerance. However, little is known about the relative contribution of B7 molecules, tryptophan degrading enzymes, as well as the impact of tumor and stromal cell interactions to the development of immunosuppressive tumor microenvironment. To investigate such interactions, we used a tripartite model of human hepatocellular carcinoma cell line (HepG2) and mesenchymal stromal cells (MSCs) co-cultured with peripheral blood mononuclear cells (PBMCs). Co-culture of HepG2 cells and activated PBMCs demonstrate that HepG2 cells undergo PBMC mediated cytolysis, despite constitutive expression of B7-H3 and upregulation of PD-L1 by IFNγ. Knockdown of B7-H3, PD-L1 or IDO does not modulate PBMC mediated lysis of HepG2 cells. However, TNFα preactivation enhances lysis of HepG2 cells, and blocking of TNFα production from PBMCs protects HepG2 cells. On the other hand, MSCs protect HepG2 cells from PBMC mediated lysis, even in the presence of TNFα. Further investigation showed that MSC mediated protection is associated with the unique secretome profile of upregulated and downregulated cytokines and chemokines. IFNγ activated MSCs are superior to TNFα activated or control MSCs in protecting HepG2 cells. Blockade of IFNγ driven IDO activity completely abolishes the ability of MSCs to protect HepG2 cells from cytolysis by PBMCs. These results suggest that inhibition of IFNγ activation of IDO induction in stromal cells, combined with usage of TNFα, could be a novel immunotherapeutic strategy to induce regression of hepatocellular carcinoma.
format	article
author	Raghavan Chinnadurai Amanda Paige Porter Mihir Patel Ariel Joy Lipat Mathews H. Forsberg Devi Rajan Peiman Hematti Christian M. Capitini Charles Bruker
author_facet	Raghavan Chinnadurai Amanda Paige Porter Mihir Patel Ariel Joy Lipat Mathews H. Forsberg Devi Rajan Peiman Hematti Christian M. Capitini Charles Bruker
author_sort	Raghavan Chinnadurai
title	Hepatocellular Carcinoma Cells Are Protected From Immunolysis by Mesenchymal Stromal Cells Through Indoleamine 2,3 Dioxygenase
title_short	Hepatocellular Carcinoma Cells Are Protected From Immunolysis by Mesenchymal Stromal Cells Through Indoleamine 2,3 Dioxygenase
title_full	Hepatocellular Carcinoma Cells Are Protected From Immunolysis by Mesenchymal Stromal Cells Through Indoleamine 2,3 Dioxygenase
title_fullStr	Hepatocellular Carcinoma Cells Are Protected From Immunolysis by Mesenchymal Stromal Cells Through Indoleamine 2,3 Dioxygenase
title_full_unstemmed	Hepatocellular Carcinoma Cells Are Protected From Immunolysis by Mesenchymal Stromal Cells Through Indoleamine 2,3 Dioxygenase
title_sort	hepatocellular carcinoma cells are protected from immunolysis by mesenchymal stromal cells through indoleamine 2,3 dioxygenase
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/99ee81a0e482403ab182d77d66ad8b4a
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Hepatocellular Carcinoma Cells Are Protected From Immunolysis by Mesenchymal Stromal Cells Through Indoleamine 2,3 Dioxygenase

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