Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer

Immune checkpoint inhibitors can improve the prognosis of patients with advanced malignancy; however, only a small subset of advanced colorectal cancer patients in microsatellite-instability-high or mismatch-repair-deficient colorectal cancer can benefit from immunotherapy. Unfortunately, the mechan...

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Autores principales:	Hongji Zhang, Yu Wang, Amblessed Onuma, Jiayi He, Han Wang, Yujia Xia, Rhea Lal, Xiang Cheng, Gyulnara Kasumova, Zhiwei Hu, Meihong Deng, Joal D. Beane, Alex C. Kim, Hai Huang, Allan Tsung
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	neutrophils extracellular traps programmed cell death protein 1 (PD-1) CD8+ T cells DNase I Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/d03d5215526a4b78bf8b3f90f9e5f9bf
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spelling	oai:doaj.org-article:d03d5215526a4b78bf8b3f90f9e5f9bf2021-11-11T15:28:33ZNeutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer10.3390/cancers132153332072-6694https://doaj.org/article/d03d5215526a4b78bf8b3f90f9e5f9bf2021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5333https://doaj.org/toc/2072-6694Immune checkpoint inhibitors can improve the prognosis of patients with advanced malignancy; however, only a small subset of advanced colorectal cancer patients in microsatellite-instability-high or mismatch-repair-deficient colorectal cancer can benefit from immunotherapy. Unfortunately, the mechanism behind this ineffectiveness is unclear. The tumor microenvironment plays a critical role in cancer immunity, and may contribute to the inhibition of immune checkpoint inhibitors and other novel immunotherapies in patients with advanced cancer. Herein, we demonstrate that the DNase I enzyme plays a pivotal role in the degradation of NETs, significantly dampening the resistance to anti-PD-1 blockade in a mouse colorectal cancer model by attenuating tumor growth. Remarkably, DNase I decreases tumor-associated neutrophils and the formation of MC38 tumor cell-induced neutrophil extracellular trap formation in vivo. Mechanistically, the inhibition of neutrophil extracellular traps with DNase I results in the reversal of anti-PD-1 blockade resistance through increasing CD8+ T cell infiltration and cytotoxicity. These findings signify a novel approach to targeting the tumor microenvironment using DNase I alone or in combination with immune checkpoint inhibitors.Hongji ZhangYu WangAmblessed OnumaJiayi HeHan WangYujia XiaRhea LalXiang ChengGyulnara KasumovaZhiwei HuMeihong DengJoal D. BeaneAlex C. KimHai HuangAllan TsungMDPI AGarticleneutrophils extracellular trapsprogrammed cell death protein 1 (PD-1)CD8+ T cellsDNase INeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5333, p 5333 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	neutrophils extracellular traps programmed cell death protein 1 (PD-1) CD8+ T cells DNase I Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	neutrophils extracellular traps programmed cell death protein 1 (PD-1) CD8+ T cells DNase I Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Hongji Zhang Yu Wang Amblessed Onuma Jiayi He Han Wang Yujia Xia Rhea Lal Xiang Cheng Gyulnara Kasumova Zhiwei Hu Meihong Deng Joal D. Beane Alex C. Kim Hai Huang Allan Tsung Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer
description	Immune checkpoint inhibitors can improve the prognosis of patients with advanced malignancy; however, only a small subset of advanced colorectal cancer patients in microsatellite-instability-high or mismatch-repair-deficient colorectal cancer can benefit from immunotherapy. Unfortunately, the mechanism behind this ineffectiveness is unclear. The tumor microenvironment plays a critical role in cancer immunity, and may contribute to the inhibition of immune checkpoint inhibitors and other novel immunotherapies in patients with advanced cancer. Herein, we demonstrate that the DNase I enzyme plays a pivotal role in the degradation of NETs, significantly dampening the resistance to anti-PD-1 blockade in a mouse colorectal cancer model by attenuating tumor growth. Remarkably, DNase I decreases tumor-associated neutrophils and the formation of MC38 tumor cell-induced neutrophil extracellular trap formation in vivo. Mechanistically, the inhibition of neutrophil extracellular traps with DNase I results in the reversal of anti-PD-1 blockade resistance through increasing CD8+ T cell infiltration and cytotoxicity. These findings signify a novel approach to targeting the tumor microenvironment using DNase I alone or in combination with immune checkpoint inhibitors.
format	article
author	Hongji Zhang Yu Wang Amblessed Onuma Jiayi He Han Wang Yujia Xia Rhea Lal Xiang Cheng Gyulnara Kasumova Zhiwei Hu Meihong Deng Joal D. Beane Alex C. Kim Hai Huang Allan Tsung
author_facet	Hongji Zhang Yu Wang Amblessed Onuma Jiayi He Han Wang Yujia Xia Rhea Lal Xiang Cheng Gyulnara Kasumova Zhiwei Hu Meihong Deng Joal D. Beane Alex C. Kim Hai Huang Allan Tsung
author_sort	Hongji Zhang
title	Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer
title_short	Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer
title_full	Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer
title_fullStr	Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer
title_full_unstemmed	Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer
title_sort	neutrophils extracellular traps inhibition improves pd-1 blockade immunotherapy in colorectal cancer
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/d03d5215526a4b78bf8b3f90f9e5f9bf
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Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer

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