Squamous penile cancer (PeCa) displays a rare human papillomavirus (HPV)-associated tumor entity. Investigations on the molecular pathogenesis of HPV-driven PeCa are impaired by the rareness of clinical specimens and, in particular, missing relevant cell culture models. Here, we identified in HPV-positive PeCa cell lines that HPV16 oncoproteins control p63 expression by modulating critical regulators, while integration into the p63 open reading frame facilitates oncogene expression. The resulting feed-forward loop leads to elevated p63 levels that in turn enhance the release of the neutrophil-recruiting chemokine CXCL8. Remarkably, elevated CXCL8 amounts lead to the increased surface exposition of the Fc receptor of human IgA antibodies, FcαRI, on neutrophils and correlated with a higher susceptibility to antibody-dependent neutrophil-mediated cytotoxicity (ADCC) using an EGFR (epidermal growth factor receptor)-specific IgA2 antibody. Immunohistochemical staining of tissue microarrays proved that elevated expression of p63 together with neutrophil infiltration were significantly more frequent in HPV-positive PeCa displaying a higher tumor grade. In summary, we identified a promising marker profile of PeCa patients at higher risk for worse prognosis. However, these patients may benefit from immunotherapeutic approaches efficiently engaging neutrophils for tumor cell killing.
Molecular cancer therapeutics. 2020 Dec 03 [Epub ahead of print]
Muriel Charlotte Bernhard, Anabel Zwick, Tobias Mohr, Gilles Gasparoni, Oybek Khalmurzaev, Vladimir Borisovich Matveev, Philine Loertzer, Alexey Pryalukhin, Arndt Hartmann, Carol-Immanuel Geppert, Hagen Loertzer, Heiko Wunderlich, Carsten Maik Naumann, Holger Kalthoff, Kerstin Junker, Sigrun Smola, Stefan Lohse
Institute of Virology, University of Saarland., Department of Genetics, University of Saarland., Department of Urology, Federal State Budgetary Institution., Cancer Research, Institute of Carcinogenesis., Dept of Urology, Saarland University., Institute of Pathology, University Medical Centre Bonn., Pathology, Friedrich-Alexander-University Erlangen-Nürnberg., Pathology, University Hospital Erlangen., Department of Urology and Pediatric Urology, Westpfalz Klinikum., Department of Urology and Pediatric Urology, St. Georg Klinikum., Department of Urology and Pediatric Urology, University Hospital Schleswig-Holstein., Institute for Experimental Cancer Research, Christian-Albrechts Univ., Institute of Virology, Saarland University Medical Center., Institute of Virology, University of Saarland .