Abstract A36: CXCL14-mediated antigen-specific CD8+ T-cell responses suppress HPV-positive head and neck cancer

Abstract

Abstract Human papillomaviruses (HPVs) cause over 5% of all human cancer incidences, including a subset of head and neck squamous cell carcinoma (HNSCC), resulting in about half a million deaths every year. Persistent infection with high-risk HPV is necessary for development of HPV-associated malignancies. To establish persistence in the host, HPV must evade host antiviral defenses, including the innate and adaptive immune responses. As antiviral and antitumor immune responses share similar mechanisms, it is likely that HPV-induced immune suppression leads to immune evasion and survival of HPV-infected cancer cells. We have previously shown that expression of the chemokine CXCL14 is significantly downregulated by promoter methylation mediated by the HPV oncoprotein E7 during cancer progression. Restoration of CXCL14 expression in HPV-positive HNSCC cells dramatically suppresses tumor growth through an immune-dependent mechanism in mice. While CXCL14 recruits NK and CD8+ T cells to the tumor microenvironment, the roles of NK and T cells to enact the CXCL14-mediated tumor suppression remained undefined. To determine the roles of NK and CD8+ T cells, tumor growth was assessed in wild-type C57BL/6 mice depleted of NK or CD8+ T cells and CD8-knockout mice injected with the HPV-positive HNSCC cells re-expressing CXCL14. The results show that that CD8+ T cells are required for CXCL14-mediated tumor suppression. The antitumor CD8+ T-cell responses require antigen specificity as a transgenic model of mice with a restricted CD8+ T-cell receptor failed to control tumor growth. Counteracting the HPV-mediated downregulation of major histocompatibility complex class I (MHC-I), CXCL14 expression restores MHC-I expression on HPV-positive HNSCC cells. Furthermore, knockdown of MHC-I expression in CXCL14 expressing HNSCC cells results in loss of tumor suppression, defining a critical role for antigen presentation. These results suggest that CXCL14 expression drives antigen-specific CD8+ T-cell responses and suppresses tumor growth through the restoration of MHC-I expression in HPV-positive HNSCC. Our findings provide useful insight into the CXCL14-mediated antitumor mechanism that increases CD8+ T-cell recognition of tumor cells and could boost the efficacy of current immunotherapies. Citation Format: Joseph A. Westrich, Daniel W. Vermeer, Stephanie Bonney, Alexa Silva, Jennifer N. Berger, Marianna Madeo, Louis Cicchini, John H. Lee, William C. Spanos, Dohun Pyeon. CXCL14-mediated antigen-specific CD8+ T-cell responses suppress HPV-positive head and neck cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A36.