Abstract 1587: Stress keratin 17 overexpression downregulates CD8+ T cell infiltration in papillomavirus-associated disease

Abstract High-risk human papillomaviruses (HPVs) cause 5% of human cancers. Despite the availability of HPV vaccines, there remains a strong urgency to find ways to treat persistent HPV infections, as current HPV vaccines are not therapeutic for individuals already infected. It has not well understood how papillomaviruses evade host immune surveillance to establish long-term infections, which can lead to neoplastic disease including cancer. Using a mouse papillomavirus (MmuPV1) infection model in immunocompetent FVB/N mice, we found that stress keratins are upregulated in mouse papillomavirus-induced papillomas. In mice deficient for stress keratin K17 (K17KO), we observed early regression of papillomas dependent on T-cells. Expression of cellular genes involved in immune response were significantly upregulated in the papillomas arising on the K17KO mice correlating with increased numbers of infiltrating CD8+T cells and upregulation of IFNγ-related genes, including CXCL9 and CXCL10, prior to complete regression. This T cell-dependent regression also required ligand accessibility to CXCR3, a receptor for CXCL9 and CXCL10. By analyzing public available TCGA data, we found an inverse correlation between K17 mRNA expression and CD8A, GZMB and CXCL9 mRNA expression in a cohort of head and neck cancer patients. We validated these observations by antibody immunofluorescence staining of a tissue microarray (TMA) composed of 380 tumor tissues from head and neck cancer patients (HPV+ n=265, HPV- n=49, HPV unknown n=66). We stained TMA with CD8 and K17. Out of 380 cancer specimens, there are n=46 that had either high percentage of CD8+ cells in tumor (Z score>=1.64, n=14) or a high mean fluorescence intensity of K17 (Z score>=1.64, n=33). The heatmap of these 46 samples showed that the high K17 stained tissue and high CD8+ T cell infiltrated tissues are mutually exclusive, consistent with our prior analysis from TCGA mRNA data from head and neck cancer patients. In the process of exploring the mechanism of K17-mediated immunosuppression, we found that mouse papillomas arising from K17 knockout mice lacked nuclear staining for YAP1 whereas a significant amount of nuclear staining for YAP1 was observed in WT FVB papillomas, suggesting K17 may regulate Yap1 activation to mediate downstream immunosuppressive effect. Citation Format: Wei Wang, Ellery Gronski, Paul Lambert. Stress keratin 17 overexpression downregulates CD8+ T cell infiltration in papillomavirus-associated disease [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1587.