Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer

Background Immune checkpoint inhibitors (ICIs), including anti-PD-1 therapy, have limited efficacy in patients with microsatellite stable (MSS) colorectal cancer (CRC). Interleukin 17A (IL-17A) activity leads to a protumor microenvironment, dependent on its ability to induce the production of inflam...

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Autores principales:	Chao Liu, Yang Yao, Jiaqi Shi, Ruiqi Liu, Bojun Wang, Jie Lian, Haoxiu Sun, Chunhui Zhang, Lin Fang, Xin Guan, Shuling Han, Fei Zhan, Shengnan Luo, Yuanfei Yao, Tongsen Zheng, Yanqiao Zhang
Formato:	article
Lenguaje:	EN
Publicado:	BMJ Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/1543fccbb7ab42599845ba4d1df732b1
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spelling	oai:doaj.org-article:1543fccbb7ab42599845ba4d1df732b12021-11-20T11:00:08ZBlocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer10.1136/jitc-2020-0018952051-1426https://doaj.org/article/1543fccbb7ab42599845ba4d1df732b12021-01-01T00:00:00Zhttps://jitc.bmj.com/content/9/1/e001895.fullhttps://doaj.org/toc/2051-1426Background Immune checkpoint inhibitors (ICIs), including anti-PD-1 therapy, have limited efficacy in patients with microsatellite stable (MSS) colorectal cancer (CRC). Interleukin 17A (IL-17A) activity leads to a protumor microenvironment, dependent on its ability to induce the production of inflammatory mediators, mobilize myeloid cells and reshape the tumor environment. In the present study, we aimed to investigate the role of IL-17A in resistance to antitumor immunity and to explore the feasibility of anti-IL-17A combined with anti-PD-1 therapy in MSS CRC murine models.Methods The expression of programmed cell death-ligand 1 (PD-L1) and its regulation by miR-15b-5p were investigated in MSS CRC cell lines and tissues. The effects of miR-15b-5p on tumorigenesis and anti-PD-1 treatment sensitivity were verified both in vitro and in colitis-associated cancer (CAC) and APCmin/+ murine models. In vivo efficacy and mechanistic studies were conducted using antibodies targeting IL-17A and PD-1 in mice bearing subcutaneous CT26 and MC38 tumors.Results Evaluation of clinical pathological specimens confirmed that PD-L1 mRNA levels are associated with CD8+ T cell infiltration and better prognosis. miR-15b-5p was found to downregulate the expression of PD-L1 at the protein level, inhibit tumorigenesis and enhance anti-PD-1 sensitivity in CAC and APCmin/+ CRC models. IL-17A led to high PD-L1 expression in CRC cells through regulating the P65/NRF1/miR-15b-5p axis. Combined IL-17A and PD-1 blockade had efficacy in CT26 and MC38 tumors, with more cytotoxic T lymphocytes cells and fewer myeloid-derived suppressor cells in tumors.Conclusions IL-17A increases PD-L1 expression through the p65/NRF1/miR-15b-5p axis and promotes resistance to anti-PD-1 therapy. Blocking IL-17A improved the efficacy of anti-PD-1 therapy in MSS CRC murine models. IL-17A might serve as a therapeutic target to sensitize patients with MSS CRC to ICI therapy.Chao LiuYang YaoJiaqi ShiRuiqi LiuBojun WangJie LianHaoxiu SunChunhui ZhangLin FangXin GuanShuling HanFei ZhanShengnan LuoYuanfei YaoTongsen ZhengYanqiao ZhangBMJ Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal for ImmunoTherapy of Cancer, Vol 9, Iss 1 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Chao Liu Yang Yao Jiaqi Shi Ruiqi Liu Bojun Wang Jie Lian Haoxiu Sun Chunhui Zhang Lin Fang Xin Guan Shuling Han Fei Zhan Shengnan Luo Yuanfei Yao Tongsen Zheng Yanqiao Zhang Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer
description	Background Immune checkpoint inhibitors (ICIs), including anti-PD-1 therapy, have limited efficacy in patients with microsatellite stable (MSS) colorectal cancer (CRC). Interleukin 17A (IL-17A) activity leads to a protumor microenvironment, dependent on its ability to induce the production of inflammatory mediators, mobilize myeloid cells and reshape the tumor environment. In the present study, we aimed to investigate the role of IL-17A in resistance to antitumor immunity and to explore the feasibility of anti-IL-17A combined with anti-PD-1 therapy in MSS CRC murine models.Methods The expression of programmed cell death-ligand 1 (PD-L1) and its regulation by miR-15b-5p were investigated in MSS CRC cell lines and tissues. The effects of miR-15b-5p on tumorigenesis and anti-PD-1 treatment sensitivity were verified both in vitro and in colitis-associated cancer (CAC) and APCmin/+ murine models. In vivo efficacy and mechanistic studies were conducted using antibodies targeting IL-17A and PD-1 in mice bearing subcutaneous CT26 and MC38 tumors.Results Evaluation of clinical pathological specimens confirmed that PD-L1 mRNA levels are associated with CD8+ T cell infiltration and better prognosis. miR-15b-5p was found to downregulate the expression of PD-L1 at the protein level, inhibit tumorigenesis and enhance anti-PD-1 sensitivity in CAC and APCmin/+ CRC models. IL-17A led to high PD-L1 expression in CRC cells through regulating the P65/NRF1/miR-15b-5p axis. Combined IL-17A and PD-1 blockade had efficacy in CT26 and MC38 tumors, with more cytotoxic T lymphocytes cells and fewer myeloid-derived suppressor cells in tumors.Conclusions IL-17A increases PD-L1 expression through the p65/NRF1/miR-15b-5p axis and promotes resistance to anti-PD-1 therapy. Blocking IL-17A improved the efficacy of anti-PD-1 therapy in MSS CRC murine models. IL-17A might serve as a therapeutic target to sensitize patients with MSS CRC to ICI therapy.
format	article
author	Chao Liu Yang Yao Jiaqi Shi Ruiqi Liu Bojun Wang Jie Lian Haoxiu Sun Chunhui Zhang Lin Fang Xin Guan Shuling Han Fei Zhan Shengnan Luo Yuanfei Yao Tongsen Zheng Yanqiao Zhang
author_facet	Chao Liu Yang Yao Jiaqi Shi Ruiqi Liu Bojun Wang Jie Lian Haoxiu Sun Chunhui Zhang Lin Fang Xin Guan Shuling Han Fei Zhan Shengnan Luo Yuanfei Yao Tongsen Zheng Yanqiao Zhang
author_sort	Chao Liu
title	Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer
title_short	Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer
title_full	Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer
title_fullStr	Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer
title_full_unstemmed	Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer
title_sort	blocking il-17a enhances tumor response to anti-pd-1 immunotherapy in microsatellite stable colorectal cancer
publisher	BMJ Publishing Group
publishDate	2021
url	https://doaj.org/article/1543fccbb7ab42599845ba4d1df732b1
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Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer

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