Programmed death receptor (PD-)1/PD-ligand (L)1 in urological cancers : the “all-around warrior” in immunotherapy

• Published in: Molecular cancer Vol. 23; no. 1; pp. 183 - 26
• Main Authors: Liu, Qiang, Guan, Yujing, Li, Shenglong
• Format: Journal Article
• Language: English
• Published: England BioMed Central 02.09.2024; BMC
• Subjects: Animals; B7-H1 Antigen - metabolism; Combination therapy; Humans; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy - methods; PD-1; PD-L1; Programmed Cell Death 1 Receptor - metabolism; Regulatory mechanism; Review; Signal Transduction - drug effects; Tumor Escape; Tumor immunity; Urologic Neoplasms - drug therapy; Urologic Neoplasms - etiology; Urologic Neoplasms - immunology; Urologic Neoplasms - metabolism; Urologic Neoplasms - pathology; Urologic Neoplasms - therapy; PD-L1; Tumor immunity; Combination therapy; PD-1; Regulatory mechanism
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-024-02095-8

Programmed death receptor-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1) are essential molecules that are key in modulating immune responses. PD-L1 is constitutively expressed on various immune cells, epithelial cells, and cancer cells, where it functions as a co-stimulatory molecule capable of impairing T-cell mediated immune responses. Upon binding to PD-1 on activated T-cells, the PD-1/PD-L1 interaction triggers signaling pathways that can induce T-cell apoptosis or anergy, thereby facilitating the immune escape of tumors. In urological cancers, including bladder cancer (BCa), renal cell carcinoma (RCC), and prostate cancer (PCa), the upregulation of PD-L1 has been demonstrated. It is linked to poor prognosis and enhanced tumor immune evasion. Recent studies have highlighted the significant role of the PD-1/PD-L1 axis in the immune escape mechanisms of urological cancers. The interaction between PD-L1 and PD-1 on T-cells further contributes to immunosuppression by inhibiting T-cell activation and proliferation. Clinical applications of PD-1/PD-L1 checkpoint inhibitors have shown promising efficacy in treating advanced urological cancers, significantly improving patient outcomes. However, resistance to these therapies, either intrinsic or acquired, remains a significant challenge. This review aims to provide a comprehensive overview of the role of the PD-1/PD-L1 signaling pathway in urological cancers. We summarize the regulatory mechanism underlying PD-1 and PD-L1 expression and activity, including genetic, epigenetic, post-transcriptional, and post-translational modifications. Additionally, we discuss current clinical research on PD-1/PD-L1 inhibitors, their therapeutic potential, and the challenges associated with resistance. Understanding these mechanisms is crucial for developing new strategies to overcome therapeutic limitations and enhance the efficacy of cancer immunotherapy.