TY - JOUR
T1 - Macrophage-derived neuropilin-2 exhibits novel tumor-promoting functions
AU - Roy, Sohini
AU - Bag, Arup K.
AU - Dutta, Samikshan
AU - Polavaram, Navatha Shree
AU - Islam, Ridwan
AU - Schellenburg, Samuel
AU - Banwait, Jasjit
AU - Guda, Chittibabu
AU - Ran, Sophia
AU - Hollingsworth, Michael A.
AU - Singh, Rakesh K.
AU - Talmadge, James E.
AU - Muders, Michael H.
AU - Batra, Surinder K.
AU - Datta, Kaustubh
N1 - Funding Information:
The study was supported by R01-NIH 1R01CA182435-01A1, The Nebraska Center for Cellular Signaling CoBRE Developmental Grant P30 GM106397, Pancreatic Tumor Microenvironment Network (TMEN) U54CA163120-03, Pancreas SPORE Developmental Research Program 2013 RFA, UNMC P50 CA127297, Fred and Pamela Buffet Cancer Center Support Grant from NCI (P30CA036727), German Research Foundation DFG (grant MU2687/5-1), and Rudolf Becker Foundation for Prostate Cancer Research.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85054053040&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054053040&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-18-0562
DO - 10.1158/0008-5472.CAN-18-0562
M3 - Article
C2 - 30111533
AN - SCOPUS:85054053040
VL - 78
SP - 5600
EP - 5617
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 19
ER -