Currently, no established biomarkers are recommended for the routine diagnosis of penile carcinoma (PeCa). The rising incidence of this human papillomavirus (HPV)-related cancer entity highlights the need for promising candidates. The Calprotectin subunits S100A8 and S100A9 mark myeloid-derived suppressor cells in other HPV-related entities while their receptor CD147 was discussed to identify patients with PeCa at a higher risk for poor prognoses and treatment failure. We thus examined their expression using immunohistochemistry staining of PeCa specimens from 74 patients on tissue microarrays of the tumor center, the invasion front, and lymph node metastases. Notably, whereas the tumor center was significantly more intensively stained than the invasion front, lymph node metastases were thoroughly positive for both S100 subunits. An HPV-positive status combined with an S100A8+S100A9+ profile was related with an elevated risk for metastases. We observed several PeCa specimens with S100A8+S100A9+-infiltrating immune cells overlapping with CD15 marking neutrophils. The S100A8+S100A9+CD15+ profile was associated with dedifferentiated and metastasizing PeCa, predominantly of HPV-associated subtype. These data suggest a contribution of neutrophil-derived suppressor cells to the progression of HPV-driven penile carcinogenesis. CD147 was elevated, expressed in PeCa specimens, prominently at the tumor center and in HPV-positive PeCa cell lines. CD147+HPV+ PeCa specimens were with the higher-frequency metastasizing cancers. Moreover, an elevated expression of CD147 of HPV-positive PeCa cell lines correlated negatively with the susceptibility to IgA-based neutrophil-mediated tumor cell killing. Finally, stratifying patients regarding their HPV/S100A8/S100A9/CD15/CD147 profile may help identify patients with progressing cancer and tailor immunotherapeutic treatment strategies.
Frontiers in oncology. 2022 Oct 11*** epublish ***
Tobias Mohr, Anabel Zwick, Muriel Charlotte Hans, Isabelle Ariane Bley, Felix Leon Braun, Oybek Khalmurzaev, Vsevolod 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, Saarland University Medical Center, Homburg, Germany., Department of Urology and Paediatric Urology, Saarland University Medical Center, 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., Department of Urology and Paediatric Urology, Westpfalz Klinikum, Kaiserslautern, Germany., Institute of Pathology, Saarland University Medical Center, Homburg, Germany., Institute of Pathology, University Erlangen-Nuremberg, Erlangen, Germany., Department of Urology and Paediatric Urology, St. Georg Klinikum, Eisenach, Germany., Department of Urology and Paediatric Urology, University Hospital Schleswig Holstein, Kiel, Germany., Division of Molecular Oncology, Institute of Experimental Cancer Research, University Hospital Schleswig Holstein, Kiel, Germany.