Therapeutic Blocking of VEGF Binding to Neuropilin-2 Diminishes PD-L1 Expression to Activate Anti-Tumor Immunity in Prostate Cancer

ABSTRACT: Prostate cancers (PC) are largely unresponsive to immune checkpoint inhibitors and there is strong evidence that PD-L1 expression itself must be inhibited to activate anti-tumor immunity. Here, we report that neuropilin-2 (NRP2), which functions as a VEGF receptor on tumor cells, is an attractive target to activate anti-tumor immunity in prostate cancer because we demonstrate that VEGF/NRP2 signaling sustains PD-L1 expression. NRP2 depletion increased T cell activation in vitro. Inhibition of the binding of VEGF to NRP2 using a mouse specific anti-NRP2 mAb in a syngeneic model of prostate cancer that is resistant to checkpoint inhibition resulted in significant necrosis and tumor regression compared to both an anti-PD-L1 mAb and control IgG. This therapy also decreased tumor PD-L1 expression and increased immune cell infiltration. We also observed that the NRP2, VEGF-A, and VEGF-C genes are amplified in metastatic castration resistant and neuroendocrine prostate cancer (NEPC) and that NRP2high PD-L1high population in metastatic tumors had a significantly lower AR and higher NEPC scores than other populations. Therapeutic inhibition of VEGF binding to human NRP2 with a high affinity humanized mAb, which is suitable for clinical use, in organoids derived from NEPC patients also diminished PD-L1 expression and caused a significant increase in immune-mediated tumor cell killing consistent with the animal studies. These findings provide justification for the initiation of clinical trials using this novel function-blocking NRP2 mAb in prostate cancer, especially for patients with aggressive primary and metastatic cancers, where blocking NRP2-VEGF signaling shows potential in mitigating the morbidity and mortality associated with these cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE223811 | GEO | 2024/01/01

REPOSITORIES: GEO