Therapeutic blocking of VEGF binding to neuropilin-2 diminishes PD-L1 expression to activate antitumor immunity in prostate cancer

• DOI: 10.1126/scitranslmed.ade5855
• Publication Date: 2023-05-03T17:58:34Z
• Authors: Mengdie Wang; Christi A. Wisnie...; Choua Xiong; Peter Chhoy; Hira Lal Goel; Ayush Kumar; Lihua Julie Zhu; Rui Li; Pamela A. St. Louis; Lindsay M. Ferreira; Hubert Pakula; Zhiwen Xu; Massimo Loda; Zhong Jiang; Michael A. Brehm; Arthur M. Mercurio
• Keywords: Male; Vascular Endothelial Growth Factor A; Animals; Humans; Prostatic Neoplasms; B7-H1 Antigen; 3. Good health; Neuropilin-2; Signal Transduction

Prostate cancers are largely unresponsive to immune checkpoint inhibitors (ICIs), and there is strong evidence that programmed death-ligand 1 (PD-L1) expression itself must be inhibited activate antitumor immunity. Here, we report neuropilin-2 (NRP2), which functions as a vascular endothelial growth factor (VEGF) receptor on tumor cells, an attractive target immunity in prostate cancer because VEGF-NRP2 signaling sustains PD-L1 expression. NRP2 depletion increased T cell activation vitro. In syngeneic model of resistant ICI, inhibition the binding VEGF using mouse-specific anti-NRP2 monoclonal antibody (mAb) resulted necrosis regression compared with both anti–PD-L1 mAb control immunoglobulin G. This therapy also decreased infiltration. We observed , VEGFA VEGFC genes amplified metastatic castration-resistant neuroendocrine cancer. found individuals High tumors had lower androgen higher scores than other organoids derived from patients cancer, therapeutic high-affinity humanized suitable for clinical use diminished caused substantial increase immune-mediated killing, consistent animal studies. These findings provide justification initiation trials this function-blocking especially aggressive disease.