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 to activate antitumor immunity.
Here, we report that neuropilin-2 (NRP2), which functions as a vascular endothelial growth factor (VEGF) receptor on tumor cells, is an attractive target to activate antitumor immunity in prostate cancer because VEGF-NRP2 signaling sustains PD-L1 expression. NRP2 depletion increased T cell activation in vitro. In a syngeneic model of prostate cancer that is resistant to ICI, inhibition of the binding of VEGF to NRP2 using a mouse-specific anti-NRP2 monoclonal antibody (mAb) resulted in necrosis and tumor regression compared with both an anti-PD-L1 mAb and control immunoglobulin G. This therapy also decreased tumor PD-L1 expression and increased immune cell infiltration. We observed that the NRP2, VEGFA, and VEGFC genes are amplified in metastatic castration-resistant and neuroendocrine prostate cancer. We also found that individuals with NRP2High PD-L1High metastatic tumors had lower androgen receptor expression and higher neuroendocrine prostate cancer scores than other individuals with prostate cancer. In organoids derived from patients with neuroendocrine prostate cancer, therapeutic inhibition of VEGF binding to NRP2 using a high-affinity humanized mAb suitable for clinical use also diminished PD-L1 expression and caused a substantial increase in immune-mediated tumor cell killing, consistent with the animal studies. These findings provide justification for the initiation of clinical trials using this function-blocking NRP2 mAb in prostate cancer, especially for patients with aggressive disease.
Science translational medicine. 2023 May 03 [Epub]
Mengdie Wang, Christi A Wisniewski, 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
Departments of Molecular, Cell and Cancer Biology, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA., Program in Molecular Medicine, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA., Department of Neurology, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA., Department of Pathology, Cornell Weill School of Medicine, New York, NY 10065, USA., aTyr Pharma Inc., San Diego CA, 92121, USA., Department of Pathology, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA.