Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14

ABSTRACT High-risk human papillomaviruses (HPVs) are causally associated with multiple human cancers. Previous studies have shown that the HPV oncoprotein E7 induces immune suppression; however, the underlying mechanisms remain unknown. To understand the mechanisms by which HPV deregulates host immu...

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Autores principales:	Louis Cicchini, Joseph A. Westrich, Tao Xu, Daniel W. Vermeer, Jennifer N. Berger, Eric T. Clambey, Denis Lee, John I. Song, Paul F. Lambert, Robert O. Greer, John H. Lee, Dohun Pyeon
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/968814f4f50343f0bc8be64a70db166d
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spelling	oai:doaj.org-article:968814f4f50343f0bc8be64a70db166d2021-11-15T15:50:15ZSuppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL1410.1128/mBio.00270-162150-7511https://doaj.org/article/968814f4f50343f0bc8be64a70db166d2016-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00270-16https://doaj.org/toc/2150-7511ABSTRACT High-risk human papillomaviruses (HPVs) are causally associated with multiple human cancers. Previous studies have shown that the HPV oncoprotein E7 induces immune suppression; however, the underlying mechanisms remain unknown. To understand the mechanisms by which HPV deregulates host immune responses in the tumor microenvironment, we analyzed gene expression changes of all known chemokines and their receptors using our global gene expression data sets from human HPV-positive and -negative head/neck cancer and cervical tissue specimens in different disease stages. We report that, while many proinflammatory chemokines increase expression throughout cancer progression, CXCL14 is dramatically downregulated in HPV-positive cancers. HPV suppression of CXCL14 is dependent on E7 and associated with DNA hypermethylation in the CXCL14 promoter. Using in vivo mouse models, we revealed that restoration of Cxcl14 expression in HPV-positive mouse oropharyngeal carcinoma cells clears tumors in immunocompetent syngeneic mice, but not in Rag1-deficient mice. Further, Cxcl14 reexpression significantly increases natural killer (NK), CD4+ T, and CD8+ T cell infiltration into the tumor-draining lymph nodes in vivo. In vitro transwell migration assays show that Cxcl14 reexpression induces chemotaxis of NK, CD4+ T, and CD8+ T cells. These results suggest that CXCL14 downregulation by HPV plays an important role in suppression of antitumor immune responses. Our findings provide a new mechanistic understanding of virus-induced immune evasion that contributes to cancer progression. IMPORTANCE Human papillomaviruses (HPVs) are causally associated with more than 5% of all human cancers. During decades of cancer progression, HPV persists, evading host surveillance. However, little is known about the immune evasion mechanisms driven by HPV. Here we report that the chemokine CXCL14 is significantly downregulated in HPV-positive head/neck and cervical cancers. Using patient tissue specimens and cultured keratinocytes, we found that CXCL14 downregulation is linked to CXCL14 promoter hypermethylation induced by the HPV oncoprotein E7. Restoration of Cxcl14 expression in HPV-positive cancer cells clears tumors in immunocompetent syngeneic mice, but not in immunodeficient mice. Mice with Cxcl14 reexpression show dramatically increased natural killer and T cells in the tumor-draining lymph nodes. These results suggest that epigenetic downregulation of CXCL14 by HPV plays an important role in suppressing antitumor immune responses. Our findings may offer novel insights to develop preventive and therapeutic tools for restoring antitumor immune responses in HPV-infected individuals.Louis CicchiniJoseph A. WestrichTao XuDaniel W. VermeerJennifer N. BergerEric T. ClambeyDenis LeeJohn I. SongPaul F. LambertRobert O. GreerJohn H. LeeDohun PyeonAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 3 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Louis Cicchini Joseph A. Westrich Tao Xu Daniel W. Vermeer Jennifer N. Berger Eric T. Clambey Denis Lee John I. Song Paul F. Lambert Robert O. Greer John H. Lee Dohun Pyeon Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14
description	ABSTRACT High-risk human papillomaviruses (HPVs) are causally associated with multiple human cancers. Previous studies have shown that the HPV oncoprotein E7 induces immune suppression; however, the underlying mechanisms remain unknown. To understand the mechanisms by which HPV deregulates host immune responses in the tumor microenvironment, we analyzed gene expression changes of all known chemokines and their receptors using our global gene expression data sets from human HPV-positive and -negative head/neck cancer and cervical tissue specimens in different disease stages. We report that, while many proinflammatory chemokines increase expression throughout cancer progression, CXCL14 is dramatically downregulated in HPV-positive cancers. HPV suppression of CXCL14 is dependent on E7 and associated with DNA hypermethylation in the CXCL14 promoter. Using in vivo mouse models, we revealed that restoration of Cxcl14 expression in HPV-positive mouse oropharyngeal carcinoma cells clears tumors in immunocompetent syngeneic mice, but not in Rag1-deficient mice. Further, Cxcl14 reexpression significantly increases natural killer (NK), CD4+ T, and CD8+ T cell infiltration into the tumor-draining lymph nodes in vivo. In vitro transwell migration assays show that Cxcl14 reexpression induces chemotaxis of NK, CD4+ T, and CD8+ T cells. These results suggest that CXCL14 downregulation by HPV plays an important role in suppression of antitumor immune responses. Our findings provide a new mechanistic understanding of virus-induced immune evasion that contributes to cancer progression. IMPORTANCE Human papillomaviruses (HPVs) are causally associated with more than 5% of all human cancers. During decades of cancer progression, HPV persists, evading host surveillance. However, little is known about the immune evasion mechanisms driven by HPV. Here we report that the chemokine CXCL14 is significantly downregulated in HPV-positive head/neck and cervical cancers. Using patient tissue specimens and cultured keratinocytes, we found that CXCL14 downregulation is linked to CXCL14 promoter hypermethylation induced by the HPV oncoprotein E7. Restoration of Cxcl14 expression in HPV-positive cancer cells clears tumors in immunocompetent syngeneic mice, but not in immunodeficient mice. Mice with Cxcl14 reexpression show dramatically increased natural killer and T cells in the tumor-draining lymph nodes. These results suggest that epigenetic downregulation of CXCL14 by HPV plays an important role in suppressing antitumor immune responses. Our findings may offer novel insights to develop preventive and therapeutic tools for restoring antitumor immune responses in HPV-infected individuals.
format	article
author	Louis Cicchini Joseph A. Westrich Tao Xu Daniel W. Vermeer Jennifer N. Berger Eric T. Clambey Denis Lee John I. Song Paul F. Lambert Robert O. Greer John H. Lee Dohun Pyeon
author_facet	Louis Cicchini Joseph A. Westrich Tao Xu Daniel W. Vermeer Jennifer N. Berger Eric T. Clambey Denis Lee John I. Song Paul F. Lambert Robert O. Greer John H. Lee Dohun Pyeon
author_sort	Louis Cicchini
title	Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14
title_short	Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14
title_full	Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14
title_fullStr	Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14
title_full_unstemmed	Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14
title_sort	suppression of antitumor immune responses by human papillomavirus through epigenetic downregulation of cxcl14
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/968814f4f50343f0bc8be64a70db166d
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Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14

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