Suppression Of Antitumor Immune Responses By Human Papillomavirus Through Epigenetic Downregulation Of Cxcl14

Presentation: S276
Topic: Oropharynx
Type: Oral
Date: Tuesday, July 19, 2016
Session: 10:30 AM - 12:00 PM Oropharynx / HPV
Authors: Louis Cicchini1, Joseph Westrich1, Daniel Vermeer2, Jennifer Berger1, Eric Clambey1, Denis Lee1, John Song1, Paul Lambert1, Robert Greer1, John H Lee2, Dohun Pyeon1
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Institution(s): 1University of Colorado, 2Sanford Health
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High-risk human papillomaviruses (HPVs) are causally associated with multiple human cancers. 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 datasets 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 E7-dependent 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 dramatically suppresses tumor formation and growth in immunocompetent syngeneic mice, but not in Rag1-deficient mice. Further, CXCL14 re-expression 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 re-expression 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.

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