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Cancer Res. 2018 Oct 1;78(19):5600-5617. doi: 10.1158/0008-5472.CAN-18-0562. Epub 2018 Aug 15.

Macrophage-Derived Neuropilin-2 Exhibits Novel Tumor-Promoting Functions.

Author information

1
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
2
Fred and Pamela Buffet Cancer Center at University of Nebraska Medical Center, Omaha, Nebraska.
3
Institute of Pathology, University Hospital Carl Gustav Carus, University of Technology, Dresden, Germany.
4
Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska.
5
Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
6
Department of Microbiology and Pathology, University of Nebraska Medical Center, Omaha, Nebraska.
7
Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska.
8
Institute of Pathology, University Hospital Carl Gustav Carus, University of Technology, Dresden, Germany. kaustubh.datta@unmc.edu michael.muders@ukbonn.de.
9
Rudolf Becker Laboratory for Prostate Cancer Research, Center of Pathology, University of Bonn Medical Center, Bonn, Germany.
10
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska. kaustubh.datta@unmc.edu michael.muders@ukbonn.de.

Abstract

Tumor-associated macrophages (TAM) are causally associated with tumorigenesis as well as regulation of antitumor immune responses and have emerged as potential immunotherapeutic targets. Recent evidence suggests TAM phagocytose apoptotic tumor cells within the tumor microenvironment through efferocytosis in an immunologically silent manner, thus maintaining an immunosuppressed microenvironment. The signal transduction pathways coupling efferocytosis and immunosuppression are not well known. Neuropilin-2 (NRP2) is a member of the membrane-associated neuropilin family and has been reported in different immune cells but is poorly characterized. In this study, we show that NRP2 is expressed during macrophage differentiation, is induced by tumor cells, and regulates phagocytosis in macrophages. Furthermore, NRP2 in TAM promoted efferocytosis and facilitated tumor growth. Deletion of NRP2 from TAM impaired the clearance of apoptotic tumor cells and increased secondary necrosis within tumors. This resulted in a break in the immune tolerance and reinitiated antitumor immune responses, characterized by robust infiltration of CD8+ T and natural killer cells. This result suggests NRP2 may act as a molecular mediator that connects efferocytosis and immune suppression. Deletion of NRP2 in TAM downregulated several immunosuppressive and tumor-promoting genes and upregulated immunostimulatory genes in the myeloid compartment. Taken together, our study demonstrates that TAM-derived NRP2 plays a crucial role in tumor promotion through efferocytosis, opening the enticing option for the development of effective immunotherapy targeting TAM.Significance: Neuropilin-2 in macrophages promotes tumor growth by regulating efferocytosis of apoptotic tumor cells and orchestrating immune suppression.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5600/F1.large.jpg Cancer Res; 78(19); 5600-17. ©2018 AACR.

PMID:
30111533
PMCID:
PMC6168405
[Available on 2019-10-01]
DOI:
10.1158/0008-5472.CAN-18-0562

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