Abstract 6151: The investigation of a new combinatorial immunotherapy strategy to treat platinum-resistant penile cancer

Abstract Penile cancer is a rare malignancy, with penile squamous cell carcinoma (PSCC) accounting for 95% of cases. Human papillomavirus (HPV) infection plays a key role in the carcinogenesis of HPV-positive PSCC. In addition to surgical treatment, multimodal therapies combining neoadjuvant cisplatin-based chemotherapy regimen is required for advanced and metastatic PSCC. However, disease-specific survival analysis showed disappointing results after systemic treatments. To identify an alternative treatment with more favorable outcomes, we investigated the effectiveness of a new combinatorial immunotherapy strategy for refractory PSCC. Here, we identify a therapeutic role of combining poly (ADP-ribose) polymerase inhibitors (PARPi) with anti-PD1 antibody treatment in the SAP (PB-Cre4+ Smad4L/L ApcL/L PtenL/L) model of PSCC, which was the first genetically engineered mouse (GEM) model of penile cancer in our previous report (Nat Commun. 2020; PMID 32358507). Mechanistically, PARPi-induced PARP1 trapping and dsDNA micronuclei activated cGAS-STING signaling pathway in both murine derived SA (PB-Cre4+Smad4L/LApcL/L) and SAP (PB-Cre4+ Smad4L/L ApcL/L PtenL/L) cell lines. HPV overexpression greatly downregulated the expression of type I interferons (IFNα and IFNβ) and pro-inflammatory chemokines (CCL5, CXCL9, CXL10 and CXCL11), while increasing the proliferation and motility of human PSCC cell lines. Furthermore, Niraparib, an FDA approved PARP inhibitor, reversed the effect of HPV overexpression on tumor growth by upregulating the expression of IFN-α/β and PD-L1 in vivo. Overall, this study revealed that the combination therapy of Niraparib and anti-PD1 inhibits the progression of PSCC via reprogramming tumor microenvironment, offering promising strategy for the treatment of refractory PSCC. Citation Format: Yaoyin Li, Jad Chahoud, Xin Lu. The investigation of a new combinatorial immunotherapy strategy to treat platinum-resistant penile cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6151.