Immunologically programming the tumor microenvironment induces the pattern recognition receptor NLRC4-dependent antitumor immunity

Background The efficacy of cancer immunotherapy can be limited by the poor immunogenicity of cancer and the immunosuppressive tumor microenvironment (TME). Immunologically programming the TME and creating an immune-inflamed tumor phenotype is critical for improving the immune-responsiveness of cance...

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Autores principales:	Elizabeth Repasky, Harry D Bear, Fang Yuan, Xiaofei Yu, Wenjie Liu, Shixian Chen, Xueqian Cheng, Patrick A Paez, Tuanwei Sun, Chunyan Wei, Joseph W Landry, Andrew S Poklepovic, John R Subjeck, Chunqing Guo, Xiang-Yang Wang
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/8f4a5899c7754e49ab4f859993919521
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spelling	oai:doaj.org-article:8f4a5899c7754e49ab4f8599939195212021-11-16T04:30:04ZImmunologically programming the tumor microenvironment induces the pattern recognition receptor NLRC4-dependent antitumor immunity10.1136/jitc-2020-0015952051-1426https://doaj.org/article/8f4a5899c7754e49ab4f8599939195212021-01-01T00:00:00Zhttps://jitc.bmj.com/content/9/1/e001595.fullhttps://doaj.org/toc/2051-1426Background The efficacy of cancer immunotherapy can be limited by the poor immunogenicity of cancer and the immunosuppressive tumor microenvironment (TME). Immunologically programming the TME and creating an immune-inflamed tumor phenotype is critical for improving the immune-responsiveness of cancers. Here, we interrogate the immune modulator Flagrp170, engineered via incorporation of a pathogen-associated molecular pattern (ie, flagellin) into an immunostimulatory chaperone molecule, in transforming poorly immunogenic tumors and establishing a highly immunostimulatory milieu for immune augmentation.Methods Multiple murine cancer models were used to evaluate the immunostimulatory activity, antitumor potency, and potential side effects of Flagrp170 on administration into the tumors using a replication impaired adenovirus. Antibody neutralization and mice deficient in pattern recognition receptors, that is, toll-like receptor 5 (TLR5) and NOD like receptor (NLR) family caspase activation and recruitment domain (CARD) domain-containing protein 4 (NLRC4), both of which can recognize flagellin, were employed to understand the immunological mechanism of action of the Flagrp170.Results Intratumoral delivery of mouse or human version of Flagrp170 resulted in robust inhibition of multiple malignancies including head and neck squamous cell carcinoma and breast cancer, without tissue toxicities. This in situ Flagrp170 treatment induced a set of cytokines in the TME known to support Th1/Tc1-dominant antitumor immunity. Additionally, granulocyte macrophage colony-stimulating factor derived from mobilized CD8+ T cells was involved in the therapeutic activity of Flagrp170. We also made a striking finding that NLRC4, not TLR5, is required for Flagrp170-mediated antitumor immune responses.Conclusion Our results elucidate a novel immune-potentiating activity of Flagrp170 via engaging the innate pattern recognition receptor NLRC4, and support its potential clinical use to reshape cancer immune phenotype for overcoming therapeutic resistance.Elizabeth RepaskyHarry D BearFang YuanXiaofei YuWenjie LiuShixian ChenXueqian ChengPatrick A PaezTuanwei SunChunyan WeiJoseph W LandryAndrew S PoklepovicJohn R SubjeckChunqing GuoXiang-Yang WangBMJ 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 Elizabeth Repasky Harry D Bear Fang Yuan Xiaofei Yu Wenjie Liu Shixian Chen Xueqian Cheng Patrick A Paez Tuanwei Sun Chunyan Wei Joseph W Landry Andrew S Poklepovic John R Subjeck Chunqing Guo Xiang-Yang Wang Immunologically programming the tumor microenvironment induces the pattern recognition receptor NLRC4-dependent antitumor immunity
description	Background The efficacy of cancer immunotherapy can be limited by the poor immunogenicity of cancer and the immunosuppressive tumor microenvironment (TME). Immunologically programming the TME and creating an immune-inflamed tumor phenotype is critical for improving the immune-responsiveness of cancers. Here, we interrogate the immune modulator Flagrp170, engineered via incorporation of a pathogen-associated molecular pattern (ie, flagellin) into an immunostimulatory chaperone molecule, in transforming poorly immunogenic tumors and establishing a highly immunostimulatory milieu for immune augmentation.Methods Multiple murine cancer models were used to evaluate the immunostimulatory activity, antitumor potency, and potential side effects of Flagrp170 on administration into the tumors using a replication impaired adenovirus. Antibody neutralization and mice deficient in pattern recognition receptors, that is, toll-like receptor 5 (TLR5) and NOD like receptor (NLR) family caspase activation and recruitment domain (CARD) domain-containing protein 4 (NLRC4), both of which can recognize flagellin, were employed to understand the immunological mechanism of action of the Flagrp170.Results Intratumoral delivery of mouse or human version of Flagrp170 resulted in robust inhibition of multiple malignancies including head and neck squamous cell carcinoma and breast cancer, without tissue toxicities. This in situ Flagrp170 treatment induced a set of cytokines in the TME known to support Th1/Tc1-dominant antitumor immunity. Additionally, granulocyte macrophage colony-stimulating factor derived from mobilized CD8+ T cells was involved in the therapeutic activity of Flagrp170. We also made a striking finding that NLRC4, not TLR5, is required for Flagrp170-mediated antitumor immune responses.Conclusion Our results elucidate a novel immune-potentiating activity of Flagrp170 via engaging the innate pattern recognition receptor NLRC4, and support its potential clinical use to reshape cancer immune phenotype for overcoming therapeutic resistance.
format	article
author	Elizabeth Repasky Harry D Bear Fang Yuan Xiaofei Yu Wenjie Liu Shixian Chen Xueqian Cheng Patrick A Paez Tuanwei Sun Chunyan Wei Joseph W Landry Andrew S Poklepovic John R Subjeck Chunqing Guo Xiang-Yang Wang
author_facet	Elizabeth Repasky Harry D Bear Fang Yuan Xiaofei Yu Wenjie Liu Shixian Chen Xueqian Cheng Patrick A Paez Tuanwei Sun Chunyan Wei Joseph W Landry Andrew S Poklepovic John R Subjeck Chunqing Guo Xiang-Yang Wang
author_sort	Elizabeth Repasky
title	Immunologically programming the tumor microenvironment induces the pattern recognition receptor NLRC4-dependent antitumor immunity
title_short	Immunologically programming the tumor microenvironment induces the pattern recognition receptor NLRC4-dependent antitumor immunity
title_full	Immunologically programming the tumor microenvironment induces the pattern recognition receptor NLRC4-dependent antitumor immunity
title_fullStr	Immunologically programming the tumor microenvironment induces the pattern recognition receptor NLRC4-dependent antitumor immunity
title_full_unstemmed	Immunologically programming the tumor microenvironment induces the pattern recognition receptor NLRC4-dependent antitumor immunity
title_sort	immunologically programming the tumor microenvironment induces the pattern recognition receptor nlrc4-dependent antitumor immunity
publisher	BMJ Publishing Group
publishDate	2021
url	https://doaj.org/article/8f4a5899c7754e49ab4f859993919521
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Immunologically programming the tumor microenvironment induces the pattern recognition receptor NLRC4-dependent antitumor immunity

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