Macrophage-derived neuropilin-2 exhibits novel tumor-promoting functions

Sohini Roy, Arup K. Bag, Samikshan Dutta, Navatha Shree Polavaram, Ridwan Islam, Samuel Schellenburg, Jasjit Banwait, Chittibabu Guda, Sophia Ran, Michael A Hollingsworth, Rakesh K Singh, James E Talmadge, Michael H. Muders, Surinder Kumar Batra, Kaustubh Datta

Research output: Contribution to journalArticle

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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 CD8þ 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.

Original languageEnglish (US)
Pages (from-to)5600-5617
Number of pages18
JournalCancer Research
Volume78
Issue number19
DOIs
StatePublished - Oct 1 2018

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Neuropilin-2
Macrophages
Neoplasms
Neuropilins
Cytophagocytosis
Immune Tolerance
Natural Killer T-Cells
Tumor Microenvironment

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Roy, S., Bag, A. K., Dutta, S., Polavaram, N. S., Islam, R., Schellenburg, S., ... Datta, K. (2018). Macrophage-derived neuropilin-2 exhibits novel tumor-promoting functions. Cancer Research, 78(19), 5600-5617. https://doi.org/10.1158/0008-5472.CAN-18-0562

Macrophage-derived neuropilin-2 exhibits novel tumor-promoting functions. / Roy, Sohini; Bag, Arup K.; Dutta, Samikshan; Polavaram, Navatha Shree; Islam, Ridwan; Schellenburg, Samuel; Banwait, Jasjit; Guda, Chittibabu; Ran, Sophia; Hollingsworth, Michael A; Singh, Rakesh K; Talmadge, James E; Muders, Michael H.; Batra, Surinder Kumar; Datta, Kaustubh.

In: Cancer Research, Vol. 78, No. 19, 01.10.2018, p. 5600-5617.

Research output: Contribution to journalArticle

Roy, S, Bag, AK, Dutta, S, Polavaram, NS, Islam, R, Schellenburg, S, Banwait, J, Guda, C, Ran, S, Hollingsworth, MA, Singh, RK, Talmadge, JE, Muders, MH, Batra, SK & Datta, K 2018, 'Macrophage-derived neuropilin-2 exhibits novel tumor-promoting functions', Cancer Research, vol. 78, no. 19, pp. 5600-5617. https://doi.org/10.1158/0008-5472.CAN-18-0562
Roy S, Bag AK, Dutta S, Polavaram NS, Islam R, Schellenburg S et al. Macrophage-derived neuropilin-2 exhibits novel tumor-promoting functions. Cancer Research. 2018 Oct 1;78(19):5600-5617. https://doi.org/10.1158/0008-5472.CAN-18-0562
Roy, Sohini ; Bag, Arup K. ; Dutta, Samikshan ; Polavaram, Navatha Shree ; Islam, Ridwan ; Schellenburg, Samuel ; Banwait, Jasjit ; Guda, Chittibabu ; Ran, Sophia ; Hollingsworth, Michael A ; Singh, Rakesh K ; Talmadge, James E ; Muders, Michael H. ; Batra, Surinder Kumar ; Datta, Kaustubh. / Macrophage-derived neuropilin-2 exhibits novel tumor-promoting functions. In: Cancer Research. 2018 ; Vol. 78, No. 19. pp. 5600-5617.
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