Penile cancer is a rare genitourinary malignancy that is associated with poor outcomes and severely limited therapeutic options that are generally non-curative when used to treat localized disease with high-risk features or advanced disease. To address the unmet need for treatment modalities with increased effectiveness, immune-based therapies such as immune-checkpoint blockade, human papilloma virus (HPV)-directed vaccines and adoptive T cell therapies have emerged as potential treatment options for advanced penile cancer. A diverse array of immune cells such as cytotoxic T lymphocytes (CTLs), tumour-associated macrophages and myeloid-derived suppressor cells have been shown to infiltrate penile cancer tumours, with distinct immune landscapes being demonstrated in HPV-positive compared with HPV-negative tumours. Study results have also demonstrated the prognostic value of immune cells such as tumour-associated macrophages, immune markers such as programmed death ligand-1, and HPV-status in penile cancer. Taken together, these findings underscore the clinical relevance of the tumour immune microenvironment as a source of both prognostic indicators and potential therapeutic targets for immune-based therapies. Current evidence regarding the safety and efficacy of immune-based therapies is limited in penile cancer, but a number of clinical and preclinical studies are ongoing to evaluate these therapies in this disease based on promising results from studies in other malignancies, including other squamous cell carcinomas. In addition, an opportunity exists to combine immune-based therapies with existing lines of systemic therapy to offer the most benefit to patients with advanced penile cancer. Future work should focus on expansion of preclinical models for immune-based drug discovery.In this Review, Joshi and colleagues describe the immune landscape of penile cancer, examine existing and novel immune-based therapeutic targets, and discuss the future directions of immune-based therapies in penile cancer based on preclinical and clinical studies.
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