title: 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 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.
  
  
  
  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.
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Cicchini
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Westrich
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.affiliation: Cancer Biology Research Center, Sanford Research, Sioux Falls, South Dakota, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Vermeer
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Berger
authors.affiliation: Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Clambey
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Denis
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: John I
authors.initials: JI
authors.lastname: Song
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
authors.affiliation: Departments of Pathology and Dermatology and Division of Oral and Maxillofacial Pathology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Greer
authors.affiliation: Cancer Biology Research Center, Sanford Research, Sioux Falls, South Dakota, USA john.lee@sanfordhealth.org dohun.pyeon@ucdenver.edu.
authors.forename: John H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA john.lee@sanfordhealth.org dohun.pyeon@ucdenver.edu.
authors.forename: Dohun
authors.identifier: 0000-0003-1970-844X
authors.initials: D
authors.lastname: Pyeon
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors*; D019175:DNA Methylation; D004195:Disease Models, Animal; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D006258:Head and Neck Neoplasms / Q000473:pathology; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D007108:Immune Tolerance; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D027383:Papillomaviridae / Q000472:pathogenicity*; D050725:Papillomavirus E7 Proteins / Q000378:metabolism; D030361:Papillomavirus Infections / Q000276:immunology*; D011401:Promoter Regions, Genetic; D002583:Uterine Cervical Neoplasms / Q000473:pathology
chemical_list: C118056:CXCL14 protein, human; C517518:CXCL14 protein, mouse; D019743:Chemokines, CXC; D050725:Papillomavirus E7 Proteins