Abstract A07: CXCL14 expression inhibits tumor growth by reversing human papillomavirus-mediated immune suppression
Authors: Westrich Joseph A. , Cicchini Louis , Vermeer Daniel W. , Berger Jennifer N. , Clambey Eric T. , Lee John H. , Pyeon Dohun 
Published: March 2017

Abstract
Human papillomaviruses (HPVs) are causally associated with over 5% of all human cancers including ~25% of head and neck cancers (HNC) and ~100% of cervical cancers (CxCa), resulting in approximately half a million deaths every year. Furthermore, HPV-positive HNC incidence is increasing at an epidemic rate. During decades of cancer progression, HPV persists, evades host immune surveillance, and continuously contributes to host cell transformation. However, little is known about the mechanisms of disease progression driven by HPV, particularly in the context of host immunity. We recently reported that expression of the chemokine CXCL14 is epigenetically repressed by the HPV oncoprotein E7 and that restoration of CXCL14 expression in HPV-positive HNC cells suppresses tumor growth in immunocompetent syngeneic mice, but not in immunodeficient Rag1-/- mice (PMID: 27143385). We also revealed that natural killer (NK), CD4+ T, and CD8+ T cell populations were significantly decreased in tumor-draining lymph nodes (TDLNs) compared to distal lymph nodes (dLNs) of tumor bearing mice. However, Cxcl14 expression restored NK, CD4+ T, and CD8+ T cell populations in the TDLNs to similar levels observed in the dLN. To better understand the mechanism by which CXCL14 induces antitumor immune responses, we performed a large scale immune cell profiling with dLNs and TDLNs from mice injected with HPV-positive mouse oropharyngeal epithelial cells with or without Cxcl14 expression. The multicolor flow cytometry results showed that B cell populations are significantly decreased in TDLNs by Cxcl14 expression, while populations of myeloid immune cells remain largely unchanged. To determine if NK or CD8+ T cells are necessary for tumor suppression by Cxcl14, we performed antibody-based depletion of NK or CD8+ T cell populations using anti-NK1.1 antibody (clone PK136) and anti-CD8a antibody (clone GK 2.43), respectively. The data revealed that both NK and CD8+ T cells are necessary for Cxcl14 to optimally function as a tumor suppressor. Interestingly, NK cell depletion showed two distinct groups of responders and non-responders to Cxcl14 expression, while all mice with CD8+ T cell depletion developed tumor. These results suggest that NK cells may play an important role in initiation of antitumor immune responses. In contrast, adoptive transfer of lymphocytes from Cxcl14 expressing mice does not suppress tumor growth, indicating that NK and CD8+ T cells are required but not sufficient for Cxcl14-mediated antitumor immunity. As we previously showed that Cxcl14 induces chemotaxis of NK and CD8+ T cells, the chemotactic function of Cxcl14 in the tumor microenvironment might be critical for induction of antitumor immune responses. Further, our analysis of The Cancer Genome Atlas (TCGA) data showed that CXCL14 methylation status inversely correlates to patient survival. Therefore, CXCL14 may be a key communicator for antitumor immunity in the HPV-infected tumor microenvironment and could be used as a prognostic and therapeutic tool for HPV-positive HNC and CxCa patients.
Citation Format: Joseph A. Westrich, Louis Cicchini, Daniel W. Vermeer, Jennifer N. Berger, Eric T. Clambey, John H. Lee, Dohun Pyeon. CXCL14 expression inhibits tumor growth by reversing human papillomavirus-mediated immune suppression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A07.