Interplay of PD-L1, FOXP3, and CD8 in the Immune Microenvironment of Penile Squamous Cell Carcinoma: Expression Profiles and Correlations

<b>Background:</b> This study investigates the interplay between PD-L1, FOXP3+ regulatory T cells, and CD8+ cytotoxic T lymphocytes in penile squamous cell carcinoma (penile SCC), where understanding the tumor immune microenvironment is crucial. <b>Methods:</b> We analyzed 108 penile SCC specimens using tissue microarrays (528 spots). Immunohistochemistry was performed for PD-L1, FOXP3, and CD8. Expression was quantified in tumor and stromal compartments, and correlated with clinicopathological features including histological grade, HPV-associated morphology, and host inflammatory response. <b>Results:</b> PD-L1 in tumor cells positively correlated with intratumoral CD8+ (rho = 0.408, <i>P</i> < .001) and FOXP3+ T cells (rho = 0.293, <i>P</i> = .009). Peritumoral FOXP3+ and CD8+ T cells also showed a strong correlation (rho = 0.753, <i>P</i> < .001). Higher PD-L1 and intratumoral CD8+ were associated with higher histological grade (<i>P</i> < .001). HPV-associated morphology correlated with higher PD-L1 (<i>P</i> < .001) but lower FOXP3+ infiltration (<i>P</i> < .001). Intense inflammatory response was associated with increased peritumoral FOXP3+ and CD8+ T cells (<i>P</i> < .001). <b>Conclusions:</b> The immune microenvironment of penile SCC involves complex interactions among PD-L1, FOXP3+, and CD8+, and was significantly influenced by histological grade, HPV status, and inflammation. The strong co-localization of peritumoral regulatory and cytotoxic T cells suggests a critical regulatory axis. These findings highlight distinct immune profiles within penile SCC, offering insights for developing tailored immunotherapeutic strategies.