Abstract 4587: The N-terminal domain of HARS is a novel NRP2 ligand and can regulate NRP2-dependent macrophage function

Tumor-associated macrophages (TAM) are associated with regulation of antitumor immune responses, and neuropilin-2 (NRP2), a pleiotropic receptor with an emerging role in immune responses, has recently been demonstrated to be important for this activity (Roy et al, Cancer Res. 2018). Deletion of NRP2 results in impaired clearance of apoptotic tumor cells through reduced efferocytosis, which plays a role in tumor promotion. We now show that the N-terminal domain of the histidyl-tRNA synthetase (HARS) is a specific binding partner of NRP2, and can regulate the phagocytic function of NRP2 in macrophages. The HARS N-terminal domain, which is found only in higher eukaryotes, is conserved among splice variants of HARS and has evolved to regulate immune cell engagement. Incubation of macrophages with recombinant HARS N-terminal domain, had no effect on phagocytic uptake, but significantly impaired the maturation of phagosomes in a dose dependent manner. This phenotype mimics that of the NRP2 knockout, suggesting pharmacological intervention with this agent to modulate NRP2 driven biology may be possible. Citation Format: Navatha Shree Sharma, Samikshan Dutta, Steve Crampton, Sanna Rosengren, Kaustubh Datta. The N-terminal domain of HARS is a novel NRP2 ligand and can regulate NRP2-dependent macrophage function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4587.