PeCa is a rare entity with rising incidence rates due to increased infections with human papillomaviruses (HPV). The distinct subtypes of PeCa with an individual pathogenesis demand biomarkers for a precise patient risk assessment regarding disease progression and therapeutic susceptibility. We recently identified promising candidates associated with an HPV-instructed tumor microenvironment (TME) using HPV-positive PeCa cell lines and tissue microarrays (TMA). The capacity of HPV + p63 + PeCa cells to release neutrophil-attracting CXCL-8 provided a molecular link explaining the infiltration of CD15 + myeloid cells in PeCa specimens. The candidate biomarkers HPV, p63, CD15, DKK1, and CD147 linked a tumor-promoting TME with a higher TNM classification reflecting more aggressive and metastasizing cancers. Based on immune-reactive scores (IRS) from TMA staining for these biomarkers, we calculated correlations and conducted association analyses to assess the degree of relationship between all biomarkers. We then conducted Kaplan-Meier survival estimates and Cox regression analyses to delineate the impact on PeCa patient survival. There is a notable predictive potential regarding the survival of patients with biomarker profiles beyond the potency of the individual biomarker. From all candidate biomarkers and biomarker profiles, the combination of CD147 and infiltrating CD15 + cells linked to an active HPV-driven transformation displayed cancer-immune dynamics with dismal prognosis for patients. After deciphering relevant interdependencies, the HPV + CD147 + CD15 + status was the most potent profile predicting metastasis-free survival of PeCa patients. The results of this report underscore the need for analysis of the TME and the development of multi-parameter composite scores that reflect fundamental cancer-immune relationships to tailor therapeutic interventions based on actual cancer immune dynamics.
Scientific reports. 2024 Sep 27*** epublish ***
Stefan Lohse, Jan Niklas Mink, Lea Eckhart, Muriel Charlotte Hans, Leuart Jusufi, Anabel Zwick, Tobias Mohr, Isabelle Ariane Bley, Oybek Khalmurzaev, Vsevolod Borisovich Matveev, Philine Loertzer, Alexey Pryalukhin, Arndt Hartmann, Carol-Immanuel Geppert, Hagen Loertzer, Heiko Wunderlich, Hans-Peter Lenhof, Carsten Maik Naumann, Holger Kalthoff, Kerstin Junker
Institute for Virology, Saarland University Medical Center, Saarland University, Kirrberger Str. Building 47, 66421, Homburg, Germany. ., Department of Urology and Pediatric Urology, Saarland University, 66421, Homburg, Germany., Center for Bioinformatics, Saarland Informatics Campus, Saarland University, Saarbrücken, Germany., Institute for Virology, Saarland University Medical Center, Saarland University, Kirrberger Str. Building 47, 66421, Homburg, Germany., Department of Urology, Federal State Budgetary Institution "N.N. Blokhin National Medical Research Center of Oncology", Ministry of Health of the Russian Federation, Moscow, 115478, Russian Federation., Department of Urology and Pediatric Urology, Westpfalz-Klinikum, Kaiserslautern, Germany., Institute of Pathology, Saarland University Medical Centre, 66421, Homburg, Germany., Institute of Pathology, University Erlangen-Nuremberg, 91054, Erlangen, Germany., Clinic of Urology and Pediatric Urology, St. Georg Klinikum, 99817, Eisenach, Germany., Department of Urology and Pediatric Urology, University Hospital Schleswig Holstein, Kiel, Germany., Institute for Experimental Cancer Research, Medical Faculty, Christian Albrecht University, Kiel, Germany.