The HPV and p63 Status in Penile Cancer Are Linked with the Infiltration and Therapeutic Availability of Neutrophils.

Autor:	Bernhard MC; Institute of Virology, University of Saarland, Homburg, Germany., Zwick A; Institute of Virology, University of Saarland, Homburg, Germany., Mohr T; Institute of Virology, University of Saarland, Homburg, Germany., Gasparoni G; Department of Genetics, University of Saarland, Saarbrücken, Germany., Khalmurzaev O; Department of Urology and Pediatric Urology, University of Saarland, Homburg, Germany.; Department of Urology, Federal State Budgetary Institution 'N.N. Blokhin National Medical Research Center of Oncology' of the Ministry of Health of the Russian Federation, Moscow, Russia., Matveev VB; Department of Urology, Federal State Budgetary Institution 'N.N. Blokhin National Medical Research Center of Oncology' of the Ministry of Health of the Russian Federation, Moscow, Russia., Loertzer P; Department of Urology and Pediatric Urology, University of Saarland, Homburg, Germany., Pryalukhin A; Institute of Pathology, Saarland University Medical Centre, Homburg, Germany.; Institute of Pathology, University Medical Centre Bonn, Bonn, Germany., Hartmann A; Institute of Pathology, University Erlangen-Nuremberg, Erlangen, Germany., Geppert CI; Institute of Pathology, University Erlangen-Nuremberg, Erlangen, Germany., Loertzer H; Department of Urology and Pediatric Urology, Westpfalz Klinikum, Kaiserslautern, Germany., Wunderlich H; Department of Urology and Paediatric Urology, St. Georg Klinikum, Eisenach, Germany., Naumann CM; Department of Urology and Pediatric Urology, University Hospital Schleswig Holstein, Kiel, Germany., Kalthoff H; Division of Molecular Oncology, Institute of Experimental Cancer Research, University Hospital Schleswig Holstein, Kiel, Germany., Junker K; Department of Urology and Pediatric Urology, University of Saarland, Homburg, Germany., Smola S; Institute of Virology, University of Saarland, Homburg, Germany., Lohse S; Institute of Virology, University of Saarland, Homburg, Germany. stefan.lohse@uni-saarland.de.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2021 Feb; Vol. 20 (2), pp. 423-437. Date of Electronic Publication: 2020 Dec 03.
DOI:	10.1158/1535-7163.MCT-20-0173
Abstrakt:	Squamous penile cancer displays a rare human papillomavirus (HPV)-associated tumor entity. Investigations on the molecular pathogenesis of HPV-driven penile cancer are impaired by the rareness of clinical specimens and, in particular, are missing relevant cell culture models. Here, we identified in HPV-positive penile cancer cell lines that HPV16 oncoproteins control TP63 expression by modulating critical regulators, while integration into the TP63 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-specific IgA2 antibody. IHC staining of tissue microarrays proved that elevated expression of p63 together with neutrophil infiltration were significantly more frequent in HPV-positive penile cancer displaying a higher tumor grade. In summary, we identified a promising marker profile of patients with penile cancer at higher risk for worse prognosis. However, these patients may benefit from immunotherapeutic approaches efficiently engaging neutrophils for tumor cell killing. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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