Cancer cell-intrinsic PD-1: Its role in malignant progression and immunotherapy

Programmed cell death protein-1 (PD-1), also called CD279, is coded by the PDCD1 gene and is constitutively expressed on the surface of immune cells. As a receptor and immune checkpoint, PD-1 can bind to programmed death ligand-1/programmed death ligand-2 (PD-L1/PD-L2) in tumor cells, leading to tumor immune evasion. Anti-PD-1 and anti-PD-L1 are important components in tumor immune therapy. PD-1 is also expressed as an intrinsic variant (iPD-1) in cancer cells where it plays important roles in malignant progression as proposed by recent studies. However, iPD-1 has received much less attention compared to PD-1 expressed on immune cells although there is an unmet medical need for fully elucidating the mechanisms of actions to achieve the best response in tumor immunotherapy. iPD-1 suppresses tumorigenesis in non-small cell lung cancer (NSCLC) and colon cancer, whereas it promotes tumorigenesis in melanoma, hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), thyroid cancer (TC), glioblastoma (GBM), and triple-negative breast cancer (TNBC). In this review, we focus on the role of iPD-1 in tumorigenesis and development and its molecular mechanisms. We also deeply discuss nivolumab-based combined therapy in common tumor therapy. iPD-1 may explain the different therapeutic effects of anti-PD-1 treatment and provide critical information for use in combined anti-tumor approaches.