Human papillomavirus infection affects treatment outcomes and the immune microenvironment in patients with advanced penile squamous cell carcinoma receiving programmed cell death protein 1 inhibitor–based combination therapy

Abstract Background Penile squamous cell carcinoma (PSCC) is a human papillomavirus (HPV)‐associated malignancy. Immunotherapy is emerging as a potential treatment for advanced PSCC. In this study, the authors analyzed the association of HPV status with outcomes and the immune microenvironment in patients with advanced PSCC undergoing programmed cell death protein 1 (PD1) inhibitor–based combination therapy (PCT). Methods HPV status was assessed using quantitative polymerase chain reaction in 87 patients with advanced PSCC treated with PCT. Objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), and overall survival (OS) in the HPV+ and HPV– groups were compared. Additionally, bulk RNA sequencing was performed to investigate the potential impact of HPV on the immune microenvironment in advanced PSCC. Results Among patients receiving first‐line PCT, ORR (91.7% vs. 64.6%, p = .014) and DCR (100.0% vs. 79.2%, p = .025) in the HPV+ group were higher compared to the HPV– group. Kaplan–Meier curves demonstrated that the HPV+ group exhibited superior PFS ( p = .005) and OS ( p = .004) for patients in the first‐line setting. However, these advantages of HPV infection were not observed in multi‐line PCT ( p > .050). HPV status remained an independent prognostic factor for predicting better ORR ( p = .024), PFS ( p = .002), and OS ( p = .020) in the multivariate analyses. Landmark analyses showed that the HPV‐induced superiority of PFS occurred at an early stage (within 3 months) and OS occurred at a relatively late stage (within 9 months). Bioinformatic analyses identified potential immune‐activated genes (GLDC, CYP4F12, etc.) and pathways (RAGE, PI3K/AKT, etc.), antitumor immune cell subtypes, and lower tumor immune dysfunction and exclusion scores in HPV+ tissues. Conclusions HPV infection may confer treatment efficacy and survival benefits in patients with advanced PSCC receiving first‐line PCT because of the possible stimulation of the antitumor immune microenvironment. Plain Language Summary Human papillomavirus (HPV) infection may induce better objective response rate, progression‐free survival (PFS), and overall survival (OS) for advanced penile squamous cell carcinoma (PSCC) patients receiving first‐line programmed cell death protein 1 inhibitor–based combination therapy (PCT) instead of multi‐line PCT. HPV infection‐induced PFS advantage occurs at an early stage (within 3 months) whereas OS superiority occurs at a relatively late stage (within 9 months). Antitumor immune microenvironment could be stimulated by HPV infection in advanced PSCC tissues.