CXCL14 suppresses human papillomavirus-associated head and neck cancer through antigen-specific CD8+ T-cell responses by upregulating MHC-I expression

Joseph A Westrich,David Raben,John I Song,Louis Cicchini,William C Spanos,John H Lee,Alexa Silva,Jennifer N Berger,Jill E Slansky,Stephanie Bonney,Daniel W Vermeer,Robert O Greer,Dohun Pyeon

doi:10.1038/s41388-019-0911-6

Abstract

Evasion of the host immune responses is critical for both persistent human papillomavirus (HPV) infection and associated cancer progression. We have previously shown that expression of the homeostatic chemokine CXCL14 is significantly downregulated by the HPV oncoprotein E7 during cancer progression. Restoration of CXCL14 expression in HPV-positive head and neck cancer (HNC) cells dramatically suppresses tumor growth and increases survival through an immune-dependent mechanism in mice. Although CXCL14 recruits natural killer (NK) and T cells to the tumor microenvironment, the mechanism by which CXCL14 mediates tumor suppression through NK and/or T cells remained undefined. Here we report that CD8+ T cells are required for CXCL14-mediated tumor suppression. Using a CD8+ T-cell receptor transgenic model, we show that the CXCL14-mediated antitumor CD8+ T-cell responses require antigen specificity. Interestingly, CXCL14 expression restores major histocompatibility complex class I (MHC-I) expression on HPV-positive HNC cells downregulated by HPV, and knockdown of MHC-I expression in HNC cells results in loss of tumor suppression even with CXCL14 expression. These results suggest that CXCL14 enacts antitumor immunity through restoration of MHC-I expression on tumor cells and promoting antigen-specific CD8+ T-cell responses to suppress HPV-positive HNC.

Highlights

Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Human papillomaviruses (HPVs) cause over 5% of all human cancer incidences, resulting in about half a million deaths every year [1]
Our results suggest that CXCL14 enacts effective tumor suppression through recruitment of CD8+ T cells and restoration of major histocompatibility complex class I (MHC-I) antigen presentation
Tumor growth was monitored in the natural killer (NK) and CD8+ T-cell-depleted mice injected with mouse HPV

Summary

Introduction

Human papillomaviruses (HPVs) cause over 5% of all human cancer incidences, resulting in about half a million deaths every year [1]. Persistent infection with high-risk HPV is necessary for the development of HPV-associated malignancies [2], including most cervical cancers (CxCa) and an increasing number of head and neck cancers. CXCL14 suppresses human papillomavirus-associated head and neck cancer through antigen-specific. HPV must evade antiviral host defenses including the innate and adaptive immune responses. The HPV oncoproteins E5, E6, and E7 dysregulate a multitude of immune response mechanisms to avoid host immune surveillance As antiviral and antitumor immune responses share similar mechanisms [6, 7], it is likely that HPV-induced host immune evasion contributes to evasion of antitumor immune responses for cancer cell survival

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