CoChat
Sign Up
Cited by 80Phagocytosis and Immune RegulationImmune cells in cancerCancer Immunotherapy and Biomarkers

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

Open access
Roy, Sohini, Bag, Arup K., Dutta, Samikshan, Polavaram, Navatha Shree, Islam, Ridwan, Schellenburg, Samuel, Banwait, Jasjit, Guda, Chittibabu +7 more·2018·Cancer Research
DOI 10.1158/0008-5472.can-18-0562PMC PMC6168405

Published version of a preprint

Open this paper in CoChat — free account

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1158/0008-5472.can-18-0562

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 50

  1. [1]Okabe Y, Medzhitov R. Wormhole Travel for Macrophages. Cell. 2016; 165(3): 518– 9. 10.1016/j.cell.2016.04.005. PubMed PMID:. 27104973 · DOI
  2. [2]Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008; 8(12): 958– 69. doi: 10.1038/nri2448. PubMed PMID:; PMCID: PMC2724991. 19029990 PMC2724991 · DOI · Paper page
  3. [3]Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014; 6: 13 10.12703/P6-13. PubMed PMID:; PMCID: PMC3944738. 24669294 PMC3944738 · DOI · Paper page
  4. [4]Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017; 14(7): 399– 416. 10.1038/nrclinonc.2016.217. PubMed PMID:; PMCID: PMC5480600. 28117416 PMC5480600 · DOI
  5. [6]Elliott MR, Ravichandran KS. Clearance of apoptotic cells: implications in health and disease. J Cell Biol. 2010; 189(7): 1059– 70. 10.1083/jcb.201004096. PubMed PMID:; PMCID: PMC2894449. 20584912 PMC2894449 · DOI
  6. [7]Ravichandran KS. Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums. J Exp Med. 2010; 207(9): 1807– 17. 10.1084/jem.20101157. PubMed PMID:; PMCID: PMC2931173. 20805564 PMC2931173 · DOI
  7. [8]Franz S, Gaipl US, Munoz LE, Sheriff A, Beer A, Kalden JR, Herrmann M. Apoptosis and autoimmunity: when apoptotic cells break their silence. Curr Rheumatol Rep. 2006; 8(4): 245– 7. Epub 2006/07/15. PubMed PMID:. 16839503
  8. [9]Baumann I, Kolowos W, Voll RE, Manger B, Gaipl U, Neuhuber WL, Kirchner T, Kalden JR, Herrmann M. Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. Arthritis Rheum. 2002; 46(1): 191– 201. 10.1002/1529-0131(200201)46:1<191::AID-ART10027>3.0.CO;2-K. PubMed PMID:. 11817590 · DOI · Paper page
  9. [10]Munoz LE, Janko C, Chaurio RA, Schett G, Gaipl US, Herrmann M. IgG opsonized nuclear remnants from dead cells cause systemic inflammation in SLE. Autoimmunity. 2010; 43(3): 232– 5. 10.3109/08916930903510930. PubMed PMID:. 20187705 · DOI
  10. [11]Munoz LE, Janko C, Schulze C, Schorn C, Sarter K, Schett G, Herrmann M. Autoimmunity and chronic inflammation - two clearance-related steps in the etiopathogenesis of SLE. Autoimmun Rev. 2010; 10(1): 38– 42. 10.1016/j.autrev.2010.08.015. PubMed PMID:. 20817127 · DOI
  11. [12]Munoz LE, Lauber K, Schiller M, Manfredi AA, Herrmann M. The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol. 2010; 6(5): 280– 9. 10.1038/nrrheum.2010.46. PubMed PMID:. 20431553 · DOI
  12. [13]Munoz LE, Lauber K, Schiller M, Manfredi AA, Schett G, Voll RE, Herrmann M. [ The role of incomplete clearance of apoptotic cells in the etiology and pathogenesis of SLE]. Z Rheumatol. 2010; 69(2): 152, 4– 6. 10.1007/s00393-009-0603-7. PubMed PMID:. 20107814 · DOI
  13. [14]Henson PM. Cell Removal: Efferocytosis. Annu Rev Cell Dev Biol. 2017; 33: 127– 44. 10.1146/annurev-cellbio-111315-125315. PubMed PMID:. 28613937 · DOI
  14. [15]Fadok VA, Bratton DL, Guthrie L, Henson PM. Differential effects of apoptotic versus lysed cells on macrophage production of cytokines: role of proteases. J Immunol. 2001; 166(11): 6847– 54. Epub 2001/05/22. PubMed PMID:. 11359844
  15. [16]Green DR, Ferguson T, Zitvogel L, Kroemer G. Immunogenic and tolerogenic cell death. Nat Rev Immunol. 2009; 9(5): 353– 63. 10.1038/nri2545. PubMed PMID:; PMCID: PMC2818721. 19365408 PMC2818721 · DOI · Paper page
  16. [17]Stanford JC, Young C, Hicks D, Owens P, Williams A, Vaught DB, Morrison MM, Lim J, Williams M, Brantley-Sieders DM, Balko JM, Tonetti D, Earp HS 3rd, Cook RS. Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution. J Clin Invest. 2014; 124(11): 4737– 52. 10.1172/JCI76375. PubMed PMID:; PMCID: PMC4347249. 25250573 PMC4347249 · DOI
  17. [18]Kumar S, Calianese D, Birge RB. Efferocytosis of dying cells differentially modulate immunological outcomes in tumor microenvironment. Immunol Rev. 2017; 280(1): 149– 64. 10.1111/imr.12587. PubMed PMID:. 29027226 PMC8359679 · DOI
  18. [19]Birge RB, Boeltz S, Kumar S, Carlson J, Wanderley J, Calianese D, Barcinski M, Brekken RA, Huang X, Hutchins JT, Freimark B, Empig C, Mercer J, Schroit AJ, Schett G, Herrmann M. Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer. Cell Death Differ. 2016; 23(6): 962– 78. 10.1038/cdd.2016.11. PubMed PMID:; PMCID: PMC4987730. 26915293 PMC4987730 · DOI
  19. [20]Cook RS, Jacobsen KM, Wofford AM, DeRyckere D, Stanford J, Prieto AL, Redente E, Sandahl M, Hunter DM, Strunk KE, Graham DK, Earp HS 3rd., MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis. J Clin Invest. 2013; 123(8): 3231– 42. 10.1172/JCI67655. PubMed PMID:; PMCID: PMC3726162. 23867499 PMC3726162 · DOI
  20. [21]Chen X, Doffek K, Sugg SL, Shilyansky J. Phosphatidylserine regulates the maturation of human dendritic cells. Journal of immunology. 2004; 173(5): 2985– 94. Epub 2004/08/24. PubMed PMID:. 15322157
  21. [22]Roca H, Jones JD, Purica MC, Weidner S, Koh AJ, Kuo R, Wilkinson JE, Wang Y, Daignault-Newton S, Pienta KJ, Morgan TM, Keller ET, Nor JE, Shea LD, McCauley LK. Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone. J Clin Invest. 2018; 128(1): 248– 66. 10.1172/JCI92466. PubMed PMID:. 29202471 PMC5749545 · DOI
  22. [23]Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter JA, Tamagnone L, Mazzone M. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell. 2013; 24(6): 695– 709. 10.1016/j.ccr.2013.11.007. PubMed PMID:. 24332039 · DOI
  23. [24]Dai X, Okon I, Liu Z, Wu Y, Zhu H, Song P, Zou MH. A novel role for myeloid cell-specific neuropilin 1 in mitigating sepsis. FASEB J. 2017; 31(7): 2881– 92. 10.1096/fj.201601238R. PubMed PMID:; PMCID: PMC5471517. 28325756 PMC5471517 · DOI
  24. [25]Miyauchi JT, Caponegro MD, Chen D, Choi MK, Li M, Tsirka SE. Deletion of Neuropilin 1 from Microglia or Bone Marrow-Derived Macrophages Slows Glioma Progression. Cancer research. 2018; 78(3): 685– 94. 10.1158/0008-5472.CAN-17-1435. PubMed PMID:; PMCID: PMC5887044. 29097606 PMC5887044 · DOI
  25. [26]Miyauchi JT, Chen D, Choi M, Nissen JC, Shroyer KR, Djordevic S, Zachary IC, Selwood D, Tsirka SE. Ablation of Neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression. Oncotarget. 2016; 7(9): 9801– 14. 10.18632/oncotarget.6877. PubMed PMID:; PMCID: PMC4891085. 26755653 PMC4891085 · DOI
  26. [27]Roy S, Bag AK, Singh RK, Talmadge JE, Batra SK, Datta K. Multifaceted Role of Neuropilins in the Immune System: Potential Targets for Immunotherapy. Front Immunol. 2017; 8: 1228 10.3389/fimmu.2017.01228. PubMed PMID:; PMCID: PMC5641316. 29067024 PMC5641316 · DOI
  27. [28]Walz A, Rodriguez I, Mombaerts P. Aberrant sensory innervation of the olfactory bulb in neuropilin-2 mutant mice. J Neurosci. 2002; 22(10): 4025– 35. Epub 2002/05/23. doi: 20026374. PubMed PMID:. 12019322 PMC6757638
  28. [29]Mielgo A, Schmid MC. Impact of tumour associated macrophages in pancreatic cancer. BMB Rep. 2013; 46(3): 131– 8. Epub 2013/03/27. PubMed PMID:. 23527856 PMC4133870
  29. [30]Protti MP, De Monte L. Immune infiltrates as predictive markers of survival in pancreatic cancer patients. Front Physiol. 2013; 4: 210 10.3389/fphys.2013.00210. PubMed PMID:; PMCID: PMC3738865. 23950747 PMC3738865 · DOI
  30. [33]Kinchen JM, Ravichandran KS. Phagosome maturation: going through the acid test. Nat Rev Mol Cell Biol. 2008; 9(10): 781– 95. doi: 10.1038/nrm2515. PubMed PMID:; PMCID: PMC2908392. 18813294 PMC2908392 · DOI · Paper page
  31. [34]Hochreiter-Hufford A, Ravichandran KS. Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harb Perspect Biol. 2013; 5(1): a008748. doi: 10.1101/cshperspect.a008748. PubMed PMID:; PMCID: PMC3579390. 23284042 PMC3579390 · DOI · Paper page
  32. [35]Pesce J, Kaviratne M, Ramalingam TR, Thompson RW, Urban JF Jr., Cheever AW, Young DA, Collins M, Grusby MJ, Wynn TA. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J Clin Invest. 2006; 116(7): 2044– 55. 10.1172/JCI27727. PubMed PMID:; PMCID: PMC1479424. 16778988 PMC1479424 · DOI
  33. [36]Zhang Y, Davis C, Shah S, Hughes D, Ryan JC, Altomare D, Pena MM. IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis. Mol Carcinog. 2017; 56(1): 272– 87. 10.1002/mc.22491. PubMed PMID:; PMCID: PMC5630136. 27120577 PMC5630136 · DOI
  34. [37]Segaliny AI, Mohamadi A, Dizier B, Lokajczyk A, Brion R, Lanel R, Amiaud J, Charrier C, Boisson-Vidal C, Heymann D. Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment. Int J Cancer. 2015; 137(1): 73– 85. 10.1002/ijc.29376. PubMed PMID:. 25471534 · DOI · Paper page
  35. [38]Li Y, Wang L, Pappan L, Galliher-Beckley A, Shi J. IL-1beta promotes stemness and invasiveness of colon cancer cells through Zeb1 activation. Mol Cancer. 2012; 11: 87 10.1186/1476-4598-11-87. PubMed PMID:; PMCID: PMC3532073. 23174018 PMC3532073 · DOI
  36. [39]Li CW, Xia W, Huo L, Lim SO, Wu Y, Hsu JL, Chao CH, Yamaguchi H, Yang NK, Ding Q, Wang Y, Lai YJ, LaBaff AM, Wu TJ, Lin BR, Yang MH, Hortobagyi GN, Hung MC. Epithelial-mesenchymal transition induced by TNF-alpha requires NF-kappaB-mediated transcriptional upregulation of Twist1. Cancer Res. 2012; 72(5): 1290– 300. 10.1158/0008-5472.CAN-11-3123. PubMed PMID:; PMCID: PMC3350107. 22253230 PMC3350107 · DOI
  37. [40]Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 2011; 278(1): 16– 27. 10.1111/j.1742-4658.2010.07919.x. PubMed PMID:. 21087457 · DOI
  38. [41]Cathcart J, Pulkoski-Gross A, Cao J. Targeting Matrix Metalloproteinases in Cancer: Bringing New Life to Old Ideas. Genes Dis. 2015; 2(1): 26– 34. 10.1016/j.gendis.2014.12.002. PubMed PMID:; PMCID: PMC4474140. 26097889 PMC4474140 · DOI
  39. [42]Shay G, Lynch CC, Fingleton B. Moving targets: Emerging roles for MMPs in cancer progression and metastasis. Matrix Biol. 2015; 44–46: 200– 6. 10.1016/j.matbio.2015.01.019. PubMed PMID:; PMCID: PMC4564058. 25652204 PMC4564058 · DOI
  40. [43]Thind K, Padrnos LJ, Ramanathan RK, Borad MJ. Immunotherapy in pancreatic cancer treatment: a new frontier. Therap Adv Gastroenterol. 2017; 10(1): 168– 94. 10.1177/1756283X16667909. PubMed PMID:; PMCID: PMC5330603. 28286568 PMC5330603 · DOI
  41. [44]Rey-Gallardo A, Escribano C, Delgado-Martin C, Rodriguez-Fernandez JL, Gerardy-Schahn R, Rutishauser U, Corbi AL, Vega MA. Polysialylated neuropilin-2 enhances human dendritic cell migration through the basic C-terminal region of CCL21. Glycobiology. 2010; 20(9): 1139– 46. 10.1093/glycob/cwq078. PubMed PMID:. 20488940 · DOI
  42. [45]Nissen JC, Tsirka SE. Tuftsin-driven experimental autoimmune encephalomyelitis recovery requires neuropilin-1. Glia. 2016; 64(6): 923– 36. 10.1002/glia.22972. PubMed PMID:; PMCID: PMC4833601. 26880314 PMC4833601 · DOI
  43. [46]Kitano M, Nakaya M, Nakamura T, Nagata S, Matsuda M. Imaging of Rab5 activity identifies essential regulators for phagosome maturation. Nature. 2008; 453(7192): 241– 5. doi: 10.1038/nature06857. PubMed PMID:. 18385674 · DOI
  44. [47]Arandjelovic S, Ravichandran KS. Phagocytosis of apoptotic cells in homeostasis. Nat Immunol. 2015; 16(9): 907– 17. doi: 10.1038/ni.3253. PubMed PMID:; PMCID: PMC4826466. 26287597 PMC4826466 · DOI · Paper page
  45. [49]Kinchen JM, Ravichandran KS. Identification of two evolutionarily conserved genes regulating processing of engulfed apoptotic cells. Nature. 2010; 464(7289): 778– 82. 10.1038/nature08853. PubMed PMID:; PMCID: 2901565. 20305638 PMC2901565 · DOI
  46. [51]Fordham JB, Naqvi AR, Nares S. Regulation of miR-24, miR-30b, and miR-142–3p during macrophage and dendritic cell differentiation potentiates innate immunity. J Leukoc Biol. 2015; 98(2): 195– 207. 10.1189/jlb.1A1014-519RR. PubMed PMID:; PMCID: PMC4501676. 25990241 PMC4501676 · DOI
  47. [52]Naqvi AR, Fordham JB, Ganesh B, Nares S. miR-24, miR-30b and miR-142–3p interfere with antigen processing and presentation by primary macrophages and dendritic cells. Sci Rep. 2016; 6: 32925 10.1038/srep32925. PubMed PMID:; PMCID: PMC5017188. 27611009 PMC5017188 · DOI
  48. [53]Naqvi AR, Fordham JB, Nares S. miR-24, miR-30b, and miR-142–3p regulate phagocytosis in myeloid inflammatory cells. Journal of immunology. 2015; 194(4): 1916– 27. 10.4049/jimmunol.1401893. PubMed PMID:; PMCID: PMC4323870. 25601927 PMC4323870 · DOI · Paper page
  49. [54]Henson PM, Bratton DL, Fadok VA. Apoptotic cell removal. Curr Biol. 2001; 11(19): R795– 805. Epub 2001/10/10. PubMed PMID:. 11591341
  50. [55]Vonderheide RH, Bajor DL, Winograd R, Evans RA, Bayne LJ, Beatty GL. CD40 immunotherapy for pancreatic cancer. Cancer Immunol Immunother. 2013; 62(5): 949– 54. 10.1007/s00262-013-1427-5. PubMed PMID:; PMCID: PMC3731141. 23589109 PMC3731141 · DOI

Cited by

Sorted by citations

Authors
Roy, S., Bag, A. K., Dutta, S., Polavaram, N. S., Islam, R., Schellenburg, S., Banwait, J., Guda, C., Ran, S., Hollingsworth, M. A., Singh, R. K., Talmadge, J. E., Muders, M. H., Batra, S. K., & Datta, K.
Affiliations
  • Fred and Pamela Buffett Cancer Center (US)
  • University Hospital Carl Gustav Carus (DE)
  • University of Nebraska Medical Center (US)
  • SIU Medicine (US)
  • University of Bonn (DE)
Corresponding author
Datta, Kaustubh
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2018-10-01
Volume
78
Issue
19
Pages
5600-5617
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-18-0562
PMC
PMC6168405
OpenAlex
W2885789377
Cited by
80
References
5
Citations by year
2026: 5 · 2025: 7 · 2024: 7 · 2023: 16 · 2022: 20 · 2021: 7 · 2020: 12 · 2019: 6
FWCI
2.69
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH (1R01CA182435-01A1)
  • Nebraska Center for Cellular Signaling (P30 GM106397)
  • Pancreatic Tumor Microenvironment Network (U54CA163120-03)
  • NCI (P30CA036727)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
neuropilin-2, tumor-associated macrophages, efferocytosis, tumor immunosuppression, tumor growth, secondary necrosis, antitumor immunity, CD8+ T cells, natural killer cells, macrophage differentiation, tumor microenvironment, immunotherapy targets
MeSH terms
Animals, Cells, Cultured, Humans, Immune System, Immunosuppression Therapy, Immunotherapy, Leukocytes, Mononuclear, Macrophages, Mice, Inbred C57BL, Monocytes, Neoplasms, Phagocytosis, Phagosomes, Signal Transduction, Gene Expression Regulation, Neoplastic, Apoptosis, Jurkat Cells, Neuropilin-2, Cell Line, Tumor, Mice, Tumor Microenvironment, Transcriptome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review