(880.4) Studies on the function of myeloid-derived Neuropilin-1 in glioma: a focus on tumor hypoxia

Poster Board Number: E272

Daniel Radin (Stony Brook University School of Medicine), Michael Caponegro (Stony Brook University School of Medicine), Gregory Smith (Stony Brook University School of Medicine), Victoria Moushiaveshi (Stony Brook University School of Medicine), David Selwood (University College London), Stella Tsirka (Stony Brook University School of Medicine)

Glioblastoma (GB), is the most aggressive and most commonly diagnosed primary adult neoplasm in the CNS. As GB grows rapidly, it outstrips its oxygen supply, resulting in pockets of hypoxia throughout the developing tumor. Hypoxic glioma cells recruit microglia and macrophages to support angiogenesis to resolve hypoxia and promote an anti-inflammatory tumor milieu. It was previously shown in peripheral cancers that Neuropilin-1 (Nrp1) on macrophages governed entry into hypoxic niches, wherein these cells supported angiogenesis and bolstered immune evasion. We have previously shown myeloid specific Nrp1 deletion or pharmacological antagonism reduces angiogenesis and restores antitumor immunity. Herein, we demonstrate that Nrp1 deletion from myeloid cells reduces infiltration into hypoxic areas of developing gliomas. This results in an increase in tumor hypoxia and myeloid cell abundance. Additionally, we reveal that myeloid cells adopt an M2-like phenotype in hypoxic areas, but that this phenotype is abolished in areas of hypoxia when Nrp1 is deleted, supporting multiple functions of this protein in myeloid cells. Finally, we verified that pharmacological antagonism of the Nrp1 b1 domain is sufficient to increase tumor hypoxia and GAM accumulation in developing gliomas. These data further support efforts co-targeting Nrp1 and hypoxia-associated survival pathways independent of glioma driver mutations.

This work was partially supported by an NIH F30CA257677 (DPR), NIH T32 GM008444 (DPR) and a Stony Brook University Seed Grant (SET).



When Neuropilin 1 is expressed in macrophages, gliomas exhibit modest hypoxia with macrophages principally trafficking to areas of hypoxia and adapting an anti-inflammatory polarization. When Neuropilin 1 is deleted from myeloid cells, gliomas exhibit increased hypoxia and macrophage abundance. As well, macrophages traffic to areas of hypoxia with reduced frequency and do not adapt an anti-inflammatory polarization even in areas of hypoxia.