Immune Checkpoint Neuropilins as Novel Biomarkers and Therapeutic Targets for Pancreatic Cancer

SIMPLE SUMMARY: Malignant tumors, especially pancreatic cancer, are the major contributors to cancer mortality worldwide, and their effective treatments are still limited. Our study suggested that NRPs, especially NRP1, are attractive diagnostic and prognostic biomarkers, mediate immunoregulation, and have functions beyond immunology in the context of cancer. As potential novel immune checkpoints, NRPs, provide a new opportunity for tumor immunotherapy, and they will be of interest for further study. ABSTRACT: The traditional immune checkpoint blockade therapy benefits some patients with cancer, but elicits no response in certain cancers, such as pancreatic adenocarcinoma (PAAD); thus, novel checkpoints and effective targets are required. Here, we found that there was a higher Neuropilin (NRP) expression in tumor tissues as novel immune checkpoints, which was associated with poor prognosis and pessimistic responses to immune checkpoint blockade therapy. In the tumor microenvironment of PAAD samples, NRPs were widely expressed in tumor, immune and stromal cells. The relationship of NRPs with tumor immunological features in PAAD and pan-cancer was evaluated using bioinformatics methods; it was positively correlated with the infiltration of myeloid immune cells and the expression of most immune checkpoint genes. Bioinformatics analysis, in vitro and in vivo experiments suggested that NRPs exhibit potential immune-related and immune-independent pro-tumor effects. NRPs, especially NRP1, are attractive biomarkers and therapeutic targets for cancers, particularly PAAD.