Abstract 4791: Immunosuppressive myeloid cells can be modulated with NRP2-targeting antibody ATYR2810 leading to enhanced anti-tumor immunity

Abstract Introduction: A major obstacle for many cancer immunotherapies is intrinsic or acquired resistance to treatment. Myeloid-derived immune cell populations such as myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) are promoting an immunosuppressive tumor environment. This limits the effectiveness of current cancer immunotherapies. When activated, myeloid lineage immune cells express high levels of Neuropilin2 (NRP2), a single pass transmembrane protein. NRP2 forms heterodimeric complexes with other membrane receptors such as VEGF receptors, plexins and integrins. In experimental models of immune disease, NRP2 has demonstrated anti-inflammatory effects. However, the role of NRP2 on immune cells in the context of tumor biology is largely unknown. Results: NRP2 expression is upregulated on myeloid cells in an experimental model of acute lung injury and can be detected on myeloid cells in syngeneic tumor models. In experimental models of immune diseases like atopic dermatitis and collagen-induced arthritis, NRP2-deficient mice show a stronger immune response and worse pathology. Blocking NRP2 with a monoclonal antibody (ATYR2810) in a syngeneic, orthotopic mouse model of glioblastoma (GBM), resulted in anti-tumoral polarization of myeloid cells and a significant increase in overall survival. Additionally, in syngeneic tumor models with a large immunosuppressive myeloid population, ATYR2810 treatment improved the effectiveness of checkpoint inhibition via anti-PD-1. Conclusions: Here we demonstrate that NRP2 is a negative regulator of the inflammatory response and is highly expressed on immunosuppressive myeloid cells in the tumor environment. Blocking NRP2 with ATYR2810 was effective as a single therapy and when combined with checkpoint inhibition in syngeneic tumor models with a high prevalence of MDSCs. This suggests that modulating NRP2 offers a new approach to targeting and reversing the immunosuppressive function of myeloid cells in the tumor microenvironment. Citation Format: Christoph Burkart, Clara Polizzi, John Hyunkuk Choi, Max Pastenes, Alison Barber, Michael Lim, Leslie Nangle. Immunosuppressive myeloid cells can be modulated with NRP2-targeting antibody ATYR2810 leading to enhanced anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4791.