Prognostic significance and immune correlates of FADD in penile squamous cell carcinoma

Penile squamous cell carcinoma (PSCC) with a poor prognosis lacks reliable biomarkers for stratifying patients. Fas-associated death domain (FADD) could regulate cell proliferation and has shown promising diagnostic and prognostic significance in multiple cancers. However, researchers have not determined how FADD exerts its effect on PSCC. In this study, we set out to investigate the clinical features of FADD and the prognostic impact of PSCC. Additionally, we also assessed the role of affecting the immune environment in PSCC. Immunohistochemistry was carried out to evaluate the protein expression of FADD. The difference between FADD(high) and FADD(low) was explored by RNA sequencing from available cases. The immune environment evaluation of CD4, CD8, and Foxp3 was performed by immunohistochemical. In this study, we found that FADD was overexpressed in 19.6 (39/199) patients, and the overexpression of FADD was associated with phimosis (p=0.007), N stage (p<0.001), clinical stage (p=0.001), and histologic grade (p=0.005). The overexpression of FADD was an independent prognostic factor for both PFS (HR 3.976, 95% CI 2.413-6.553, p<0.001) and OS (HR 4.134, 95% CI 2.358-7.247, p<0.001). In addition, overexpression of FADD was mainly linked to T cell activation and PD-L1 expression combined with PD-L1 checkpoint in cancer. Further validation demonstrated that overexpression of FADD was positively correlated with the infiltration of Foxp3 in PSCC (p=0.0142). It is the first time to show that overexpression of FADD is an adjunct biomarker with poor prognosis in PSCC and could also serve as a tumor immune environment regulator.