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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,\n                    <jats:italic>CXCL14<\/jats:italic>\n                    is dramatically downregulated in HPV-positive cancers. HPV suppression of\n                    <jats:italic>CXCL14<\/jats:italic>\n                    is dependent on E7 and associated with DNA hypermethylation in the\n                    <jats:italic>CXCL14<\/jats:italic>\n                    promoter. Using\n                    <jats:italic>in vivo<\/jats:italic>\n                    mouse models, we revealed that restoration of\n                    <jats:italic>Cxcl14<\/jats:italic>\n                    expression in HPV-positive mouse oropharyngeal carcinoma cells clears tumors in immunocompetent syngeneic mice, but not in\n                    <jats:italic>Rag1<\/jats:italic>\n                    -deficient mice. Further,\n                    <jats:italic>Cxcl14<\/jats:italic>\n                    reexpression significantly increases natural killer (NK), CD4\n                    <jats:sup>+<\/jats:sup>\n                    T, and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell infiltration into the tumor-draining lymph nodes\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                    <jats:italic>In vitro<\/jats:italic>\n                    transwell migration assays show that\n                    <jats:italic>Cxcl14<\/jats:italic>\n                    reexpression induces chemotaxis of NK, CD4\n                    <jats:sup>+<\/jats:sup>\n                    T, and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. These results suggest that\n                    <jats:italic>CXCL14<\/jats:italic>\n                    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.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    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\n                    <jats:italic>CXCL14<\/jats:italic>\n                    is significantly downregulated in HPV-positive head\/neck and cervical cancers. Using patient tissue specimens and cultured keratinocytes, we found that\n                    <jats:italic>CXCL14<\/jats:italic>\n                    downregulation is linked to\n                    <jats:italic>CXCL14<\/jats:italic>\n                    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\n                    <jats:italic>Cxcl14<\/jats:italic>\n                    reexpression show dramatically increased natural killer and T cells in the tumor-draining lymph nodes. These results suggest that epigenetic downregulation of\n                    <jats:italic>CXCL14<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1128\/mbio.00270-16","type":"journal-article","created":{"date-parts":[[2016,5,3]],"date-time":"2016-05-03T22:08:15Z","timestamp":1462313295000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":106,"title":["Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14"],"prefix":"10.1128","volume":"7","author":[{"given":"Louis","family":"Cicchini","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph A.","family":"Westrich","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel W.","family":"Vermeer","sequence":"additional","affiliation":[{"name":"Cancer Biology Research Center, Sanford Research, Sioux Falls, South Dakota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer N.","family":"Berger","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric T.","family":"Clambey","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado School of Medicine, 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