Abstract 5144: Role of Neuropilin-2 in the maintenance of tumor associated macrophages

Abstract

Abstract Purpose: Macrophages are key regulators of the immune system and act as a bridge between the innate and adaptive arms of the host immune responses. However, they also comprise an important component of immune cell infiltrates in various solid tumor microenvironments (TME) and impede therapy. Tumor Associated Macrophages (TAMs) are inflammatory as well as pro-tumorigenic and perform key functions which aid in tumor growth, evasion of host immune surveillance, and correlate with poor prognosis in many cancers. The objective of our current study is to elucidate the role of Neuropilin-2 (NRP2), a non-tyrosine kinase receptor in TAMs and illustrate the impact of targeting the molecular pathways regulated by NRP2 in the reversal of TAM polarization and facilitation of tumor specific host immune response. Methods: Human U937 monocyte cell line, human peripheral blood monocytes as well as mouse bone marrow derived progenitors were differentiated to macrophages to investigate whether the expression of NRP2 could be induced under conditions mimicking normal tissue homeostasis, acute inflammation and TAM polarization. NRP2 expression in TAMs was also evaluated in certain human malignancies using Immunohistochemistry. Using cellular approaches and transgenic mouse model, phagocytosis assay was performed under above-mentioned conditions. Also, macrophages were stained for endocytic markers in the presence and absence of NRP2 and viewed using Confocal Microscopy. Results: We observed that NRP2 expression was induced in human and murine macrophages under conditions mimicking normal tissue homeostasis, acute inflammation and TAM polarization. Immunohistochemical analysis revealed that macrophages isolated from human malignancies also exhibited a significant expression of NRP2. Phagocytosis assay in combination with Immunofluorescence data indicated a possible defect in endocytic compartments in NRP2 depleted conditions. Conclusions: Our data demonstrate the expression of NRP2 in macrophages is induced under normal tissue homeostasis, acute inflammation as well as in macrophages invading tumor stroma. Also, we report a novel function of NRP2 in the regulation of the endosomal maturation and thereby phagocytosis in macrophages. This will elicit a favorable immune response in acute infections, but promote cancer growth by efficient processing of efferocytosed tumor cell debris. Previous reports have established that blockade of tumor cell efferocytosis suppresses TAM polarization in the TME, breaks immune tolerance and reduces metastasis. Our ongoing and future studies will establish the therapeutic impact of targeting NRP2 regulated pathways in the tumor infiltrating macrophages in combating therapy resistance. Hence, our study carries the potential to open up new strategies to selectively target and facilitate anti-tumor host immune response in multiple human malignancies. Citation Format: Sohini Roy, Samikshan Dutta, Samuel Schellenburg, James E. Talmadge, Michael Muders, Kaustubh Datta. Role of Neuropilin-2 in the maintenance of tumor associated macrophages. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5144.