Prognostic value of the tumor immune microenvironment, PD-L1 and p16INK4A in penile squamous cell carcinoma

Abstract Penile squamous cell carcinoma (PSCC) is a rare disease with limited systemic therapy strategies in advanced stages. To gain a better understanding about tumor and immune-related factors in PSCC with potential implications for future therapeutic options, we assessed T-lymphocytic tumor immune microenvironment (TIME), human papillomavirus (HPV) status, and p16 expression in a retrospective, multi-institutional cohort of 115 PSCC patients. We constructed a tissue microarray (TMA) containing cores from the tumor front (TF) and tumor center (TC) and performed immunohistochemistry (IHC) using antibodies against p16 INK4A , CD3, CD8, and PD-L1. Cluster analysis based on CD3, CD8, and PD-L1 expression revealed two distinct immunophenotypic subgroups. The non-inflamed cluster with low expression of CD3, CD8, and PD-L1, and the inflamed cluster with high expression of these markers. Specific clustering configurations involving IHC assessments from TC highlighted a significantly shorter overall survival and cancer-specific survival for the inflamed cluster compared to the non-inflamed cluster. PD-L1 tumor proportion score (TPS) was higher in cases with vascular and lymphatic invasion, whereas combined positive score (CPS) was higher in samples with lymphatic invasion and lymph node metastasis. p16 INK4A negative cases showed higher PD-L1 TPS/CPS and reduced metastasis free survival compared to p16 INK4A positive samples. Taken together, this study demonstrates the prognostic value of the TIME using the three widely available markers CD3, CD8, and PD-L1 in PSCC. Furthermore, it provides additional evidence for a survival benefit of p16 INK4A positive cases, compared to p16 INK4A negative cases.