The HPV and p63 status in penile cancer are linked with the infiltration and therapeutic availability of neutrophils.

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.