Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment

While neutrophil extracellular traps (NETs) are important for directly promoting cancer growth, little is known about their impact on immune cells within the tumor microenvironment (TME). We hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. He...

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Autores principales:	Christof Kaltenmeier, Hamza O. Yazdani, Kristin Morder, David A. Geller, Richard L. Simmons, Samer Tohme
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	neutrophil extracellular traps tumor microenvironment T cell exhaustion T cell dysfunction program death-ligand 1 PD-L1 Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/5348aaf05b064dc9b2d68480273e0038
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spelling	oai:doaj.org-article:5348aaf05b064dc9b2d68480273e00382021-11-30T19:11:36ZNeutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment1664-322410.3389/fimmu.2021.785222https://doaj.org/article/5348aaf05b064dc9b2d68480273e00382021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.785222/fullhttps://doaj.org/toc/1664-3224While neutrophil extracellular traps (NETs) are important for directly promoting cancer growth, little is known about their impact on immune cells within the tumor microenvironment (TME). We hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. Herein, to induce a NET-rich TME, we performed liver Ischemia/Reperfusion (I/R) in an established cancer metastasis model or directly injected NETs in subcutaneous tumors. In this NET-rich TME, the majority of CD4+ and CD8+ tumor infiltrating lymphocytes expressed multiple inhibitory receptors, in addition these cells showed a functional and metabolic exhausted phenotype. Targeting of NETs in vivo by treating mice with DNAse lead to decreased tumor growth, decreased NET formation and higher levels of functioning T cells. In vitro, NETs contained the immunosuppressive ligand PD-L1 responsible for T cell exhaustion and dysfunction; an effect abrogated by using PD-L1 KO NETs or culturing NETs with PD-1 KO T cells. Furthermore, we found elevated levels of sPDL-1 and MPO-DNA, a NET marker, in the serum of patients undergoing surgery for colorectal liver metastases resection. Neutrophils isolated from patients after surgery were primed to form NETs and induced exhaustion and dysfunction of human CD4+ and CD8+ T cells. We next targeted PD-L1 in vivo by injecting a blocking antibody during liver I/R. A single dose of anti-PD-L1 during surgery lead to diminished tumors at 3 weeks and functional T cells in the TME. Our data thus reveal that NETs have the capability of suppressing T cell responses through metabolic and functional exhaustion and thereby promote tumor growth. Furthermore, targeting of PD-L1 containing NETs at time of surgery with DNAse or anti-PD-L1 lead to diminished tumor growth, which represents a novel and viable strategy for sustaining immune competence within the TME.Christof KaltenmeierHamza O. YazdaniKristin MorderDavid A. GellerRichard L. SimmonsSamer TohmeFrontiers Media S.A.articleneutrophil extracellular trapstumor microenvironmentT cell exhaustionT cell dysfunctionprogram death-ligand 1PD-L1Immunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	neutrophil extracellular traps tumor microenvironment T cell exhaustion T cell dysfunction program death-ligand 1 PD-L1 Immunologic diseases. Allergy RC581-607
spellingShingle	neutrophil extracellular traps tumor microenvironment T cell exhaustion T cell dysfunction program death-ligand 1 PD-L1 Immunologic diseases. Allergy RC581-607 Christof Kaltenmeier Hamza O. Yazdani Kristin Morder David A. Geller Richard L. Simmons Samer Tohme Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment
description	While neutrophil extracellular traps (NETs) are important for directly promoting cancer growth, little is known about their impact on immune cells within the tumor microenvironment (TME). We hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. Herein, to induce a NET-rich TME, we performed liver Ischemia/Reperfusion (I/R) in an established cancer metastasis model or directly injected NETs in subcutaneous tumors. In this NET-rich TME, the majority of CD4+ and CD8+ tumor infiltrating lymphocytes expressed multiple inhibitory receptors, in addition these cells showed a functional and metabolic exhausted phenotype. Targeting of NETs in vivo by treating mice with DNAse lead to decreased tumor growth, decreased NET formation and higher levels of functioning T cells. In vitro, NETs contained the immunosuppressive ligand PD-L1 responsible for T cell exhaustion and dysfunction; an effect abrogated by using PD-L1 KO NETs or culturing NETs with PD-1 KO T cells. Furthermore, we found elevated levels of sPDL-1 and MPO-DNA, a NET marker, in the serum of patients undergoing surgery for colorectal liver metastases resection. Neutrophils isolated from patients after surgery were primed to form NETs and induced exhaustion and dysfunction of human CD4+ and CD8+ T cells. We next targeted PD-L1 in vivo by injecting a blocking antibody during liver I/R. A single dose of anti-PD-L1 during surgery lead to diminished tumors at 3 weeks and functional T cells in the TME. Our data thus reveal that NETs have the capability of suppressing T cell responses through metabolic and functional exhaustion and thereby promote tumor growth. Furthermore, targeting of PD-L1 containing NETs at time of surgery with DNAse or anti-PD-L1 lead to diminished tumor growth, which represents a novel and viable strategy for sustaining immune competence within the TME.
format	article
author	Christof Kaltenmeier Hamza O. Yazdani Kristin Morder David A. Geller Richard L. Simmons Samer Tohme
author_facet	Christof Kaltenmeier Hamza O. Yazdani Kristin Morder David A. Geller Richard L. Simmons Samer Tohme
author_sort	Christof Kaltenmeier
title	Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment
title_short	Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment
title_full	Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment
title_fullStr	Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment
title_full_unstemmed	Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment
title_sort	neutrophil extracellular traps promote t cell exhaustion in the tumor microenvironment
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/5348aaf05b064dc9b2d68480273e0038
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Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment

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