Neuropilin 1: Function and therapeutic potential in cancer

Cancer Immunology, Immunotherapy

Volumn 63, Issue 2, 2014, Pages 81-99

  Chaudhary, Belal ^a   Khaled, Yazan S ^a,b   Ammori, Basil J ^a,b   Elkord, Eyad ^a,b,c  

^a UNIVERSITY OF SALFORD   (United Kingdom)

^b UNIVERSITY OF MANCHESTER   (United Kingdom)

^c UNITED ARAB EMIRATES UNIVERSITY   (United Arab Emirates)

Author keywords

Cancer; Neuropilin 1; Plasmacytoid dendritic cells; T regulatory cells; Therapeutic target

Indexed keywords

ANIMALS; DENDRITIC CELLS; HUMANS; LYMPHOCYTE ACTIVATION; NEOPLASMS; NEUROPILIN-1; PROTO-ONCOGENE PROTEINS C-MET; SEMAPHORIN-3A; SEMAPHORINS; T-LYMPHOCYTES, REGULATORY; TRANSFORMING GROWTH FACTOR BETA; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 84894464381     PISSN: 03407004     EISSN: 14320851     Source Type: Journal    
DOI: 10.1007/s00262-013-1500-0     Document Type: Review

References (147)

1. Cimato T, Beers J, Ding S, Ma M, McCoy JP, Boehm M, Nabel EG (2009) Neuropilin-1 identifies endothelial precursors in human and murine embryonic stem cells before CD34 expression. Circulation 119(16):2170-2178. doi: 10.1161/CIRCULATIONAHA.109.849596
2. Frankel P, Pellet-Many C, Lehtolainen P, D'Abaco GM, Tickner ML, Cheng L, Zachary IC (2008) Chondroitin sulphate-modified neuropilin 1 is expressed in human tumour cells and modulates 3D invasion in the U87MG human glioblastoma cell line through a p130Cas-mediated pathway. EMBO Rep 9(10):983-989. doi: 10.1038/embor.2008.151
3. Nakamura F, Goshima Y (2002) Structural and functional relation of neuropilins. Adv Exp Med Biol 515:55-69
4. Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S, Buck DW, Schmitz J (2000) BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol 165(11):6037-6046
5. Romeo PH, Lemarchandel V, Tordjman R (2002) Neuropilin-1 in the immune system. Adv Exp Med Biol 515:49-54
6. Tordjman R, Lepelletier Y, Lemarchandel V, Cambot M, Gaulard P, Hermine O, Romeo PH (2002) A neuronal receptor, neuropilin-1, is essential for the initiation of the primary immune response. Nat Immunol 3(5):477-482. doi: 10.1038/ni789
7. Herzog Y, Kalcheim C, Kahane N, Reshef R, Neufeld G (2001) Differential expression of neuropilin-1 and neuropilin-2 in arteries and veins. Mech Dev 109(1):115-119
8. Battaglia A, Buzzonetti A, Monego G, Peri L, Ferrandina G, Fanfani F, Scambia G, Fattorossi A (2008) Neuropilin-1 expression identifies a subset of regulatory T cells in human lymph nodes that is modulated by preoperative chemoradiation therapy in cervical cancer. Immunology 123(1):129-138. doi: 10.1111/j.1365-2567.2007.02737.x
9. Prud'homme GJ, Glinka Y (2012) Neuropilins are multifunctional coreceptors involved in tumor initiation, growth, metastasis and immunity. Oncotarget 3(9):921-939
10. Gu C, Limberg BJ, Whitaker GB, Perman B, Leahy DJ, Rosenbaum JS, Ginty DD, Kolodkin AL (2002) Characterization of neuropilin-1 structural features that confer binding to semaphorin 3A and vascular endothelial growth factor 165. J Biol Chem 277(20):18069-18076. doi: 10.1074/jbc.M201681200
11. Roth L, Nasarre C, Dirrig-Grosch S, Aunis D, Cremel G, Hubert P, Bagnard D (2008) Transmembrane domain interactions control biological functions of neuropilin-1. Mol Biol Cell 19(2):646-654. doi: 10.1091/mbc.E07-06-0625
12. Lanahan A, Zhang X, Fantin A, Zhuang Z, Rivera-Molina F, Speichinger K, Prahst C, Zhang J, Wang Y, Davis G, Toomre D, Ruhrberg C, Simons M (2013) The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis. Dev Cell 25(2):156-168. doi: 10.1016/j.devcel.2013.03.019
13. Seerapu HR, Borthakur S, Kong N, Agrawal S, Drazba J, Vasanji A, Fantin A, Ruhrberg C, Buck M, Horowitz A (2013) The cytoplasmic domain of neuropilin-1 regulates focal adhesion turnover. FEBS Lett. doi: 10.1016/j.febslet.2013.08.040
14. Janssen BJ, Malinauskas T, Weir GA, Cader MZ, Siebold C, Jones EY (2012) Neuropilins lock secreted semaphorins onto plexins in a ternary signaling complex. Nat Struct Mol Biol 19(12):1293-1299. doi: 10.1038/nsmb.2416
15. Djordjevic S, Driscoll PC (2013) Targeting VEGF signalling via the neuropilin co-receptor. Drug Discov Today 18(9-10):447-455. doi: 10.1016/j.drudis.2012.11.013
16. Soker S, Miao HQ, Nomi M, Takashima S, Klagsbrun M (2002) VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding. J Cell Biochem 85(2):357-368
17. Glinka Y, Prud'homme GJ (2008) Neuropilin-1 is a receptor for transforming growth factor beta-1, activates its latent form, and promotes regulatory T cell activity. J Leukoc Biol 84(1):302-310. doi: 10.1189/jlb.0208090
18. Glinka Y, Stoilova S, Mohammed N, Prud'homme GJ (2011) Neuropilin-1 exerts co-receptor function for TGF-beta-1 on the membrane of cancer cells and enhances responses to both latent and active TGF-beta. Carcinogenesis 32(4):613-621. doi: 10.1093/carcin/bgq281
19. Schuch G, Machluf M, Bartsch G Jr, Nomi M, Richard H, Atala A, Soker S (2002) In vivo administration of vascular endothelial growth factor (VEGF) and its antagonist, soluble neuropilin-1, predicts a role of VEGF in the progression of acute myeloid leukemia in vivo. Blood 100(13):4622-4628. doi: 10.1182/blood.V100.13.4622
20. Gagnon ML, Bielenberg DR, Gechtman Z, Miao HQ, Takashima S, Soker S, Klagsbrun M (2000) Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: in vivo expression and antitumor activity. Proc Natl Acad Sci USA 97(6):2573-2578. doi: 10.1073/pnas.040337597
21. Lu Y, Xiang H, Liu P, Tong RR, Watts RJ, Koch AW, Sandoval WN, Damico LA, Wong WL, Meng YG (2009) Identification of circulating neuropilin-1 and dose-dependent elevation following anti-neuropilin-1 antibody administration. MAbs 1(4):364-369
22. Cackowski FC, Xu L, Hu B, Cheng SY (2004) Identification of two novel alternatively spliced Neuropilin-1 isoforms. Genomics 84(1):82-94. doi: 10.1016/j.ygeno.2004.02.001
23. Uniewicz KA, Cross MJ, Fernig DG (2011) Exogenous recombinant dimeric neuropilin-1 is sufficient to drive angiogenesis. J Biol Chem 286(1):12-23. doi: 10.1074/jbc.M110.190801
24. Yazdani U, Terman JR (2006) The semaphorins. Genome Biol 7(3):211. doi: 10.1186/gb-2006-7-3-211
25. Lepelletier Y, Moura IC, Hadj-Slimane R, Renand A, Fiorentino S, Baude C, Shirvan A, Barzilai A, Hermine O (2006) Immunosuppressive role of semaphorin-3A on T cell proliferation is mediated by inhibition of actin cytoskeleton reorganization. Eur J Immunol 36(7):1782-1793. doi: 10.1002/eji.200535601
26. Delgoffe GM, Woo SR, Turnis ME, Gravano DM, Guy C, Overacre AE, Bettini ML, Vogel P, Finkelstein D, Bonnevier J, Workman CJ, Vignali DA (2013) Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin- 4a axis. Nature 501(7466):252-256. doi: 10.1038/nature12428
27. Bao P, Kodra A, Tomic-Canic M, Golinko MS, Ehrlich HP, Brem H (2009) The role of vascular endothelial growth factor in wound healing. J Surg Res 153(2):347-358. doi: 10.1016/j.jss.2008.04.023
28. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380(6573):435-439. doi: 10.1038/380435a0
29. Lee S, Chen TT, Barber CL, Jordan MC, Murdock J, Desai S, Ferrara N, Nagy A, Roos KP, Iruela-Arispe ML (2007) Autocrine VEGF signaling is required for vascular homeostasis. Cell 130(4):691-703. doi: 10.1016/j.cell.2007.06.054
30. Carmeliet P (2005) VEGF as a key mediator of angiogenesis in cancer. Oncology 69(Suppl 3):4-10. doi: 10.1159/000088478
31. Fuh G, Garcia KC, de Vos AM (2000) The interaction of neuropilin-1 with vascular endothelial growth factor and its receptor flt-1. J Biol Chem 275(35):26690-26695. doi: 10.1074/jbc.M003955200
32. Prahst C, Heroult M, Lanahan AA, Uziel N, Kessler O, Shraga-Heled N, Simons M, Neufeld G, Augustin HG (2008) Neuropilin-1-VEGFR-2 complexing requires the PDZ-binding domain of neuropilin-1. J Biol Chem 283(37):25110-25114. doi: 10.1074/jbc.C800137200
33. Mac Gabhann F, Popel AS (2005) Differential binding of VEGF isoforms to VEGF receptor 2 in the presence of neuropilin-1: a computational model. Am J Physiol Heart Circ Physiol 288(6):H2851-H2860. doi: 10.1152/ajpheart.0 1218.2004
34. Ruffini F, D'Atri S, Lacal PM (2013) Neuropilin-1 expression promotes invasiveness of melanoma cells through vascular endothelial growth factor receptor-2-dependent and -independent mechanisms. Int J Oncol 43(1):297-306. doi: 10.3892/ijo 2013.1948
35. Shintani Y, Takashima S, Asano Y, Kato H, Liao Y, Yamazaki S, Tsukamoto O, Seguchi O, Yamamoto H, Fukushima T, Sugahara K, Kitakaze M, Hori M (2006) Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling. EMBO J 25(13):3045-3055. doi: 10.1038/sj.emboj.7601188
36. Mac Gabhann F, Popel AS (2006) Targeting neuropilin-1 to inhibit VEGF signaling in cancer: comparison of therapeutic approaches. PLoS Comput Biol 2(12):e180. doi: 10.1371/journal.pcbi.0020180
37. Li MO, Sanjabi S, Flavell RA (2006) Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25(3):455-471. doi: 10.1016/j.immuni.2006.07.011
38. Blobe GC, Schiemann WP, Lodish HF (2000) Role of transforming growth factor beta in human disease. N Engl J Med 342(18):1350-1358. doi: 10.1056/NEJM200005043421807
39. Massague J (2008) TGFbeta in cancer. Cell 134(2):215-230. doi: 10.1016/j.cell.2008.07.001
40. Tran DQ (2012) TGF-beta: the sword, the wand, and the shield of FOXP3(+) regulatory T cells. J Mol Cell Biol 4(1):29-37. doi: 10.1093/jmcb/mjr033
41. Rizzolio S, Rabinowicz N, Rainero E, Lanzetti L, Serini G, Norman J, Neufeld G, Tamagnone L (2012) Neuropilin-1-dependent regulation of EGF-receptor signaling. Cancer Res 72(22):5801-5811. doi: 10.1158/0008-5472.CAN-12-0995
42. Sulpice E, Plouet J, Berge M, Allanic D, Tobelem G, Merkulova-Rainon T (2008) Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity. Blood 111(4):2036-2045. doi: 10.1182/blood-2007-04- 084269
43. Matsushita A, Gotze T, Korc M (2007) Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1. Cancer Res 67(21):10309-10316. doi: 10.1158/0008-5472.CAN-07-3256
44. Banerjee S, Sengupta K, Dhar K, Mehta S, D'Amore PA, Dhar G, Banerjee SK (2006) Breast cancer cells secreted platelet-derived growth factor-induced motility of vascular smooth muscle cells is mediated through neuropilin-1. Mol Carcinog 45(11):871-880. doi: 10.1002/mc.20248
45. Pellet-Many C, Frankel P, Evans IM, Herzog B, Junemann-Ramirez M, Zachary IC (2011) Neuropilin-1 mediates PDGF stimulation of vascular smooth muscle cell migration and signalling via p130Cas. Biochem J 435(3):609-618. doi: 10.1042/BJ20100580
46. Ball SG, Bayley C, Shuttleworth CA, Kielty CM (2010) Neuropilin-1 regulates platelet-derived growth factor receptor signalling in mesenchymal stem cells. Biochem J 427(1):29-40. doi: 10.1042/BJ20091512
47. Snuderl M, Batista A, Kirkpatrick ND, Ruiz de Almodovar C, Riedemann L, Walsh EC, Anolik R, Huang Y, Martin JD, Kamoun W, Knevels E, Schmidt T, Farrar CT, Vakoc BJ, Mohan N, Chung E, Roberge S, Peterson T, Bais C, Zhelyazkova BH, Yip S, Hasselblatt M, Rossig C, Niemeyer E, Ferrara N, Klagsbrun M, Duda DG, Fukumura D, Xu L, Carmeliet P, Jain RK (2013) Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152(5):1065-1076. doi: 10.1016/j.cell.2013.01.036
48. West DC, Rees CG, Duchesne L, Patey SJ, Terry CJ, Turnbull JE, Delehedde M, Heegaard CW, Allain F, Vanpouille C, Ron D, Fernig DG (2005) Interactions of multiple heparin binding growth factors with neuropilin-1 and potentiation of the activity of fibroblast growth factor-2. J Biol Chem 280(14):13457-13464. doi: 10.1074/jbc.M410924200
49. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155(3):1151-1164
50. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA (2001) CD4+ CD25 high regulatory cells in human peripheral blood. J Immunol 167(3):1245-1253
51. Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat Immunol 4(4):330-336. doi: 10.1038/ni904
52. Fehervari Z, Sakaguchi S (2004) Development and function of CD25+ CD4+ regulatory T cells. Curr Opin Immunol 16(2):203-208. doi: 10.1016/j.coi.2004.01. 004
53. Curotto de Lafaille MA, Lafaille JJ (2009) Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 30(5):626-635. doi: 10.1016/j.immuni.2009.05.002
54. Wing K, Sakaguchi S (2010) Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 11(1):7-13. doi: 10.1038/ni.1818
55. Andersson J, Tran DQ, Pesu M, Davidson TS, Ramsey H, O'Shea JJ, Shevach EM (2008) CD4+ FoxP3+ regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner. J Exp Med 205(9):1975-1981. doi: 10.1084/jem.20080308
56. Karlsson F, Robinson-Jackson SA, Gray L, Zhang S, Grisham MB (2011) Ex vivo generation of regulatory T cells: characterization and therapeutic evaluation in a model of chronic colitis. Methods Mol Biol 677:47-61. doi: 10.1007/978-1-60761-869-0-4
57. Haribhai D, Williams JB, Jia S, Nickerson D, Schmitt EG, Edwards B, Ziegelbauer J, Yassai M, Li SH, Relland LM, Wise PM, Chen A, Zheng YQ, Simpson PM, Gorski J, Salzman NH, Hessner MJ, Chatila TA, Williams CB (2011) A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity 35(1):109-122. doi: 10.1016/j.immuni.2011.03.029
58. Bruder D, Probst-Kepper M, Westendorf AM, Geffers R, Beissert S, Loser K, von Boehmer H, Buer J, Hansen W (2004) Neuropilin-1: a surface marker of regulatory T cells. Eur J Immunol 34(3):623-630. doi: 10.1002/eji.200324799
59. Corbel C, Lemarchandel V, Thomas-Vaslin V, Pelus AS, Agboton C, Romeo PH (2007) Neuropilin 1 and CD25 co-regulation during early murine thymic differentiation. Dev Comp Immunol 31(11):1082-1094. doi: 10.1016/j.dci.2007.01. 009
60. Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey-Bucktrout S, Anthony BA, Sverdrup FM, Head R, Kuster DJ, Ruminski P, Weiss D, Von Schack D, Bluestone JA (2012) Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med 209(10):1713-1722, S1711-1719. doi: 10.1084/jem.20120822
61. Weiss JM, Bilate AM, Gobert M, Ding Y, Curotto de Lafaille MA, Parkhurst CN, Xiong H, Dolpady J, Frey AB, Ruocco MG, Yang Y, Floess S, Huehn J, Oh S, Li MO, Niec RE, Rudensky AY, Dustin ML, Littman DR, Lafaille JJ (2012) Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Exp Med 209 (10):1723-1742, S1721. doi: 10.1084/jem.20120914
62. Solomon BD, Mueller C, Chae WJ, Alabanza LM, Bynoe MS (2011) Neuropilin-1 attenuates autoreactivity in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 108(5):2040-2045. doi: 10.1073/pnas.1008721108
63. Furtado GC, Olivares-Villagomez D, Curotto de Lafaille MA, Wensky AK, Latkowski JA, Lafaille JJ (2001) Regulatory T cells in spontaneous autoimmune encephalomyelitis. Immunol Rev 182:122-134
64. Milpied P, Renand A, Bruneau J, Mendes-da-Cruz DA, Jacquelin S, Asnafi V, Rubio MT, MacIntyre E, Lepelletier Y, Hermine O (2009) Neuropilin-1 is not a marker of human Foxp3+ Treg. Eur J Immunol 39(6):1466-1471. doi: 10.1002/eji.200839040
65. Battaglia A, Buzzonetti A, Baranello C, Ferrandina G, Martinelli E, Fanfani F, Scambia G, Fattorossi A (2009) Metastatic tumour cells favour the generation of a tolerogenic milieu in tumour draining lymph node in patients with early cervical cancer. Cancer Immunol Immunother 58(9):1363-1373. doi: 10.1007/s00262-008-0646-7
66. Xq E, Meng HX, Cao Y, Zhang SQ, Bi ZG, Yamakawa M (2012) Distribution of regulatory T cells and interaction with dendritic cells in the synovium of rheumatoid arthritis. Scand J Rheumatol 41(6):413-420. doi: 10.3109/03009742. 2012.696135
67. Yadav M, Stephan S, Bluestone JA (2013) Peripherally induced tregs - role in immune homeostasis and autoimmunity. Front Immunol 4:232. doi: 10.3389/fimmu.2013.00232
68. Piechnik A, Dmoszynska A, Omiotek M, Mlak R, Kowal M, Stilgenbauer S, Bullinger L, Giannopoulos K (2013) The VEGF receptor, neuropilin-1 (NRP1) represents a promising novel target for chronic lymphocytic leukemia patients. Int J Cancer. doi: 10.1002/ijc.28135
69. Ghez D, Lepelletier Y, Lambert S, Fourneau JM, Blot V, Janvier S, Arnulf B, van Endert PM, Heveker N, Pique C, Hermine O (2006) Neuropilin-1 is involved in human T-cell lymphotropic virus type 1 entry. J Virol 80(14):6844-6854. doi: 10.1128/JVI.02719-05
70. Booth NJ, McQuaid AJ, Sobande T, Kissane S, Agius E, Jackson SE, Salmon M, Falciani F, Yong K, Rustin MH, Akbar AN, Vukmanovic-Stejic M (2010) Different proliferative potential and migratory characteristics of human CD4+ regulatory T cells that express either CD45RA or CD45RO. J Immunol 184(8):4317-4326. doi: 10.4049/jimmunol.0903781
71. Dzionek A, Inagaki Y, Okawa K, Nagafune J, Rock J, Sohma Y, Winkels G, Zysk M, Yamaguchi Y, Schmitz J (2002) Plasmacytoid dendritic cells: from specific surface markers to specific cellular functions. Hum Immunol 63(12):1133-1148
72. Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, Srivastava M, Divekar DP, Beaton L, Hogan JJ, Fagarasan S, Liston A, Smith KG, Vinuesa CG (2011) Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 17(8):975-982. doi: 10.1038/nm.2425
73. Lin X, Chen M, Liu Y, Guo Z, He X, Brand D, Zheng SG (2013) Advances in distinguishing natural from induced Foxp3(+) regulatory T cells. Int J Clin Exp Pathol 6(2):116-123
74. Sugimoto N, Oida T, Hirota K, Nakamura K, Nomura T, Uchiyama T, Sakaguchi S (2006) Foxp3-dependent and -independent molecules specific for CD25+ CD4+ natural regulatory T cells revealed by DNA microarray analysis. Int Immunol 18(8):1197-1209. doi: 10.1093/intimm/dxl060
75. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, Shevach EM (2010) Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol 184(7):3433-3441. doi: 10.4049/jimmunol.0904028
76. Himmel ME, MacDonald KG, Garcia RV, Steiner TS, Levings MK (2013) Helios+ and Helios cells coexist within the natural FOXP3+ T regulatory cell subset in humans. J Immunol 190(5):2001-2008. doi: 10.4049/jimmunol.1201379
77. Dhamne C, Chung Y, Alousi AM, Cooper LJ, Tran DQ (2013) Peripheral and thymic foxp3(+) regulatory T cells in search of origin, distinction, and function. Front Immunol 4:253. doi: 10.3389/fimmu.2013.00253
78. Akimova T, Beier UH, Wang L, Levine MH, Hancock WW (2011) Helios expression is a marker of T cell activation and proliferation. PLoS ONE 6(8):e24226. doi: 10.1371/journal.pone.0024226
79. Elkord E, Al-Ramadi BK (2012) Helios expression in FoxP3(+) T regulatory cells. Expert Opin Biol Ther 12(11):1423-1425. doi: 10.1517/14712598.2012.711310
80. Bourbie-Vaudaine S, Blanchard N, Hivroz C, Romeo PH (2006) Dendritic cells can turn CD4+ T lymphocytes into vascular endothelial growth factor-carrying cells by intercellular neuropilin-1 transfer. J Immunol 177(3):1460-1469
81. Yuan Q, Hong S, Shi B, Kers J, Li Z, Pei X, Xu L, Wei X, Cai M (2013) CD4(+)CD25(-)Nrp1(+) T cells synergize with rapamycin to prevent murine cardiac allorejection in immunocompetent recipients. PLoS ONE 8(4):e61151. doi: 10.1371/journal.pone.0061151
82. Sarris M, Andersen KG, Randow F, Mayr L, Betz AG (2008) Neuropilin-1 expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition. Immunity 28(3):402-413. doi: 10.1016/j.immuni.2008.01.012
83. Grewal IS, Flavell RA (1996) The role of CD40 ligand in costimulation and T-cell activation. Immunol Rev 153:85-106
84. Chai JG, Xue SA, Coe D, Addey C, Bartok I, Scott D, Simpson E, Stauss HJ, Hori S, Sakaguchi S, Dyson J (2005) Regulatory T cells, derived from naive CD4+ CD25-T cells by in vitro Foxp3 gene transfer, can induce transplantation tolerance. Transplantation 79(10):1310-1316
85. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057-1061. doi: 10.1126/science.1079490
86. Fournier AE, Nakamura F, Kawamoto S, Goshima Y, Kalb RG, Strittmatter SM (2000) Semaphorin3A enhances endocytosis at sites of receptor-F-actin colocalization during growth cone collapse. J Cell Biol 149(2):411-422
87. Catalano A (2010) The neuroimmune semaphorin-3A reduces inflammation and progression of experimental autoimmune arthritis. J Immunol 185(10):6373-6383. doi: 10.4049/jimmunol.0903527
88. Kumanogoh A, Marukawa S, Suzuki K, Takegahara N, Watanabe C, Ch'ng E, Ishida I, Fujimura H, Sakoda S, Yoshida K, Kikutani H (2002) Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature 419(6907):629-633. doi: 10.1038/nature01037
89. Suzuki H, Onishi H, Wada J, Yamasaki A, Tanaka H, Nakano K, Morisaki T, Katano M (2010) VEGFR2 is selectively expressed by FOXP3high CD4+ Treg. Eur J Immunol 40(1):197-203
90. Basu A, Hoerning A, Datta D, Edelbauer M, Stack MP, Calzadilla K, Pal S, Briscoe DM (2010) Cutting edge: vascular endothelial growth factor-mediated signaling in human CD45RO+ CD4+ T cells promotes Akt and ERK activation and costimulates IFN-gamma production. J Immunol 184(2):545-549. doi: 10.4049/jimmunol.0900397
91. Terme M, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, Colussi O, Dubreuil O, Carpentier AF, Tartour E, Taieb J (2013) VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res 73(2):539-549. doi: 10.1158/0008-5472.CAN-12-2325
92. Ziogas AC, Gavalas NG, Tsiatas M, Tsitsilonis O, Politi E, Terpos E, Rodolakis A, Vlahos G, Thomakos N, Haidopoulos D, Antsaklis A, Dimopoulos MA, Bamias A (2012) VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor Type 2. Int J Cancer 130(4):857-864. doi: 10.1002/ijc.26094
93. Wang R, Wan Q, Kozhaya L, Fujii H, Unutmaz D (2008) Identification of a regulatory T cell specific cell surface molecule that mediates suppressive signals and induces Foxp3 expression. PLoS ONE 3(7):e2705. doi: 10.1371/journal.pone.0002705
94. Tran DQ, Andersson J, Wang R, Ramsey H, Unutmaz D, Shevach EM (2009) GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells. Proc Natl Acad Sci USA 106(32):13445-13450. doi: 10.1073/pnas.0901944106
95. Stockis J, Colau D, Coulie PG, Lucas S (2009) Membrane protein GARP is a receptor for latent TGF-beta on the surface of activated human Treg. Eur J Immunol 39(12):3315-3322. doi: 10.1002/eji.200939684
96. Ouyang W, Beckett O, Ma Q, Li MO (2010) Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 32(5):642-653. doi: 10.1016/j.immuni.2010.04.012
97. Marie JC, Letterio JJ, Gavin M, Rudensky AY (2005) TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+ CD25+ regulatory T cells. J Exp Med 201(7):1061-1067. doi: 10.1084/jem.20042276
98. Elkord E, Alcantar-Orozco EM, Dovedi SJ, Tran DQ, Hawkins RE, Gilham DE (2010) T regulatory cells in cancer: recent advances and therapeutic potential. Expert Opin Biol Ther 10(11):1573-1586. doi: 10.1517/14712598.2010.529126
99. Hansen W, Hutzler M, Abel S, Alter C, Stockmann C, Kliche S, Albert J, Sparwasser T, Sakaguchi S, Westendorf AM, Schadendorf D, Buer J, Helfrich I (2012) Neuropilin 1 deficiency on CD4+ Foxp3+ regulatory T cells impairs mouse melanoma growth. J Exp Med 209(11):2001-2016. doi: 10.1084/jem.20111497
100. Edelbauer M, Datta D, Vos IH, Basu A, Stack MP, Reinders ME, Sho M, Calzadilla K, Ganz P, Briscoe DM (2010) Effect of vascular endothelial growth factor and its receptor KDR on the transendothelial migration and local trafficking of human T cells in vitro and in vivo. Blood 116(11):1980-1989. doi: 10.1182/blood-2009-11-252460
101. Wang L, Zeng H, Wang P, Soker S, Mukhopadhyay D (2003) Neuropilin-1-mediated vascular permeability factor/vascular endothelial growth factor-dependent endothelial cell migration. J Biol Chem 278(49):48848-48860. doi: 10.1074/jbc.M310047200
102. Battaglia A, Buzzonetti A, Martinelli E, Fanelli M, Petrillo M, Ferrandina G, Scambia G, Fattorossi A (2010) Selective changes in the immune profile of tumor-draining lymph nodes after different neoadjuvant chemoradiation regimens for locally advanced cervical cancer. Int J Radiat Oncol Biol Phys 76(5):1546-1553. doi: 10.1016/j.ijrobp.2009.10.014
103. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18:767-811. doi: 10.1146/annurev.immunol.18.1.767
104. Hochrein H, O'Keeffe M, Wagner H (2002) Human and mouse plasmacytoid dendritic cells. Hum Immunol 63(12):1103-1110
105. Eckert F, Schmid U (1989) Identification of plasmacytoid T cells in lymphoid hyperplasia of the skin. Arch Dermatol 125(11):1518-1524
106. Hartmann E, Wollenberg B, Rothenfusser S, Wagner M, Wellisch D, Mack B, Giese T, Gires O, Endres S, Hartmann G (2003) Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res 63(19):6478-6487
107. De Wit D, Olislagers V, Goriely S, Vermeulen F, Wagner H, Goldman M, Willems F (2004) Blood plasmacytoid dendritic cell responses to CpG oligodeoxynucleotides are impaired in human newborns. Blood 103(3):1030-1032. doi: 10.1182/blood-2003-04-1216
108. Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, Leenen PJ, Liu YJ, MacPherson G, Randolph GJ, Scherberich J, Schmitz J, Shortman K, Sozzani S, Strobl H, Zembala M, Austyn JM, Lutz MB (2010) Nomenclature of monocytes and dendritic cells in blood. Blood 116(16):e74-e80. doi: 10.1182/blood-2010-02-258558
109. McKenna K, Beignon AS, Bhardwaj N (2005) Plasmacytoid dendritic cells: linking innate and adaptive immunity. J Virol 79(1):17-27. doi: 10.1128/JVI.79.1.17-27.2005
110. Gehrie E, Van der Touw W, Bromberg JS, Ochando JC (2011) Plasmacytoid dendritic cells in tolerance. Methods Mol Biol 677:127-147. doi: 10.1007/978-1-60761-869-0-9
111. Tran-Van H, Avota E, Bortlein C, Mueller N, Schneider-Schaulies S (2011) Measles virus modulates dendritic cell/T-cell communication at the level of plexinA1/neuropilin-1 recruitment and activity. Eur J Immunol 41(1):151-163. doi: 10.1002/eji.201040847
112. Mahnke K, Schmitt E, Bonifaz L, Enk AH, Jonuleit H (2002) Immature, but not inactive: the tolerogenic function of immature dendritic cells. Immunol Cell Biol 80(5):477-483. doi: 10.1046/j.1440-1711.2002.01115.x
113. Mizui M, Kikutani H (2008) Neuropilin-1: the glue between regulatory T cells and dendritic cells? Immunity 28(3):302-303. doi: 10.1016/j.immuni.2008. 02.012
114. Grage-Griebenow E, Loseke S, Kauth M, Gehlhar K, Zawatzky R, Bufe A (2007) Anti-BDCA-4 (neuropilin-1) antibody can suppress virus-induced IFN-alpha production of plasmacytoid dendritic cells. Immunol Cell Biol 85(5):383-390. doi: 10.1038/sj.icb.7100048
115. Labidi-Galy SI, Sisirak V, Meeus P, Gobert M, Treilleux I, Bajard A, Combes JD, Faget J, Mithieux F, Cassignol A, Tredan O, Durand I, Menetrier-Caux C, Caux C, Blay JY, Ray-Coquard I, Bendriss-Vermare N (2011) Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer. Cancer Res 71(16):5423-5434. doi: 10.1158/0008-5472.CAN-11-0367
116. Vermi W, Bonecchi R, Facchetti F, Bianchi D, Sozzani S, Festa S, Berenzi A, Cella M, Colonna M (2003) Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas. J Pathol 200(2):255-268. doi: 10.1002/path.1344
117. Vremec D, O'Keeffe M, Hochrein H, Fuchsberger M, Caminschi I, Lahoud M, Shortman K (2007) Production of interferons by dendritic cells, plasmacytoid cells, natural killer cells, and interferon-producing killer dendritic cells. Blood 109(3):1165-1173. doi: 10.1182/blood-2006-05-015354
118. Belardelli F, Ferrantini M, Proietti E, Kirkwood JM (2002) Interferon-alpha in tumor immunity and immunotherapy. Cytokine Growth Factor Rev 13(2):119-134
119. Golding A, Rosen A, Petri M, Akhter E, Andrade F (2010) Interferon-alpha regulates the dynamic balance between human activated regulatory and effector T cells: implications for antiviral and autoimmune responses. Immunology 131(1):107-117. doi: 10.1111/j.1365-2567.2010.03280.x
120. Kirkwood J (2002) Cancer immunotherapy: the interferon-alpha experience. Semin Oncol 29(3 Suppl 7):18-26
121. Sisirak V, Faget J, Gobert M, Goutagny N, Vey N, Treilleux I, Renaudineau S, Poyet G, Labidi-Galy SI, Goddard-Leon S, Durand I, Le Mercier I, Bajard A, Bachelot T, Puisieux A, Puisieux I, Blay JY, Menetrier-Caux C, Caux C, Bendriss-Vermare N (2012) Impaired IFN-alpha production by plasmacytoid dendritic cells favors regulatory T-cell expansion that may contribute to breast cancer progression. Cancer Res 72(20):5188-5197. doi: 10.1158/0008-5472.CAN-11- 3468
122. Gabrilovich DI, Ciernik IF, Carbone DP (1996) Dendritic cells in antitumor immune responses. I. Defective antigen presentation in tumor-bearing hosts. Cell Immunol 170(1):101-110. doi: 10.1006/cimm 1996.0139
123. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2(10):1096-1103
124. Takahashi A, Kono K, Ichihara F, Sugai H, Fujii H, Matsumoto Y (2004) Vascular endothelial growth factor inhibits maturation of dendritic cells induced by lipopolysaccharide, but not by proinflammatory cytokines. Cancer Immunol Immunother 53(6):543-550. doi: 10.1007/s00262-003-0466-8
125. Liu YJ, Blom B (2000) Introduction: TH2-inducing DC2 for immunotherapy. Blood 95(8):2482-2483
126. Wei S, Kryczek I, Zou L, Daniel B, Cheng P, Mottram P, Curiel T, Lange A, Zou W (2005) Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res 65(12):5020-5026. doi: 10.1158/0008-5472. CAN-04-4043
127. Zou W, Machelon V, Coulomb-L'Hermin A, Borvak J, Nome F, Isaeva T, Wei S, Krzysiek R, Durand-Gasselin I, Gordon A, Pustilnik T, Curiel DT, Galanaud P, Capron F, Emilie D, Curiel TJ (2001) Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat Med 7(12):1339-1346. doi: 10.1038/nm1201-1339
128. Conrad C, Gregorio J, Wang YH, Ito T, Meller S, Hanabuchi S, Anderson S, Atkinson N, Ramirez PT, Liu YJ, Freedman R, Gilliet M (2012) Plasmacytoid dendritic cells promote immunosuppression in ovarian cancer via ICOS costimulation of Foxp3(+) T-regulatory cells. Cancer Res 72(20):5240-5249. doi: 10.1158/0008-5472.CAN-12-2271
129. Faget J, Sisirak V, Blay JY, Caux C, Bendriss-Vermare N, Menetrier-Caux C (2013) ICOS is associated with poor prognosis in breast cancer as it promotes the amplification of immunosuppressive CD4 T cells by plasmacytoid dendritic cells. Oncoimmunology 2(3):e23185. doi: 10.4161/onci.23185
130. Sawant A, Hensel JA, Chanda D, Harris BA, Siegal GP, Maheshwari A, Ponnazhagan S (2012) Depletion of plasmacytoid dendritic cells inhibits tumor growth and prevents bone metastasis of breast cancer cells. J Immunol 189(9):4258-4265. doi: 10.4049/jimmunol.1101855
131. Furumoto K, Soares L, Engleman EG, Merad M (2004) Induction of potent antitumor immunity by in situ targeting of intratumoral DCs. J Clin Invest 113(5):774-783. doi: 10.1172/JCI19762
132. Amos SM, Pegram HJ, Westwood JA, John LB, Devaud C, Clarke CJ, Restifo NP, Smyth MJ, Darcy PK, Kershaw MH (2011) Adoptive immunotherapy combined with intratumoral TLR agonist delivery eradicates established melanoma in mice. Cancer Immunol Immunother 60(5):671-683. doi: 10.1007/s00262-011-0984-8
133. Liang WC, Dennis MS, Stawicki S, Chanthery Y, Pan Q, Chen Y, Eigenbrot C, Yin J, Koch AW, Wu X, Ferrara N, Bagri A, Tessier-Lavigne M, Watts RJ, Wu Y (2007) Function blocking antibodies to neuropilin-1 generated from a designed human synthetic antibody phage library. J Mol Biol 366(3):815-829. doi: 10.1016/j.jmb.2006.11.021
134. Pan Q, Chanthery Y, Liang WC, Stawicki S, Mak J, Rathore N, Tong RK, Kowalski J, Yee SF, Pacheco G, Ross S, Cheng Z, Le Couter J, Plowman G, Peale F, Koch AW, Wu Y, Bagri A, Tessier-Lavigne M, Watts RJ (2007) Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11(1):53-67. doi: 10.1016/j.ccr.2006.10.018
135. Jarvis A, Allerston CK, Jia H, Herzog B, Garza-Garcia A, Winfield N, Ellard K, Aqil R, Lynch R, Chapman C, Hartzoulakis B, Nally J, Stewart M, Cheng L, Menon M, Tickner M, Djordjevic S, Driscoll PC, Zachary I, Selwood DL (2010) Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction. J Med Chem 53(5):2215-2226. doi: 10.1021/jm901755g
136. Xin Y, Li J, Wu J, Kinard R, Weekes CD, Patnaik A, Lorusso P, Brachmann R, Tong RK, Yan Y, Watts R, Bai S, Hegde PS (2012) Pharmacokinetic and pharmacodynamic analysis of circulating biomarkers of anti-NRP1, a novel antiangiogenesis agent, in two phase I trials in patients with advanced solid tumors. Clin Cancer Res 18(21):6040-6048. doi: 10.1158/1078-0432.CCR-12-1652
137. Barr MP, Byrne AM, Duffy AM, Condron CM, Devocelle M, Harriott P, Bouchier-Hayes DJ, Harmey JH (2005) A peptide corresponding to the neuropilin-1-binding site on VEGF(165) induces apoptosis of neuropilin-1- expressing breast tumour cells. Br J Cancer 92(2):328-333. doi: 10.1038/sj.bjc.6602308
138. Teesalu T, Sugahara KN, Ruoslahti E (2013) Tumor-penetrating peptides. Front Oncol 3:216. doi: 10.3389/fonc.2013.00216
139. Teesalu T, Sugahara KN, Kotamraju VR, Ruoslahti E (2009) C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc Natl Acad Sci USA 106(38):16157-16162. doi: 10.1073/pnas.0908201106
140. Roth L, Agemy L, Kotamraju VR, Braun G, Teesalu T, Sugahara KN, Hamzah J, Ruoslahti E (2012) Transtumoral targeting enabled by a novel neuropilin-binding peptide. Oncogene 31(33):3754-3763. doi: 10.1038/onc.2011.537
141. Laakkonen P, Akerman ME, Biliran H, Yang M, Ferrer F, Karpanen T, Hoffman RM, Ruoslahti E (2004) Antitumor activity of a homing peptide that targets tumor lymphatics and tumor cells. Proc Natl Acad Sci USA 101(25):9381-9386. doi: 10.1073/pnas.0403317101
142. Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Greenwald DR, Ruoslahti E (2010) Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 328(5981):1031-1035. doi: 10.1126/science. 1183057
143. Narazaki M, Tosato G (2006) Ligand-induced internalization selects use of common receptor neuropilin-1 by VEGF165 and semaphorin3A. Blood 107(10):3892-3901. doi: 10.1182/blood-2005-10-4113
144. Bartsch G Jr, Eggert K, Soker S, Bokemeyer C, Hautmann R, Schuch G (2008) Combined antiangiogenic therapy is superior to single inhibitors in a model of renal cell carcinoma. J Urol 179(1):326-332. doi: 10.1016/j.juro.2007.08.086
145. Hong TM, Chen YL, Wu YY, Yuan A, Chao YC, Chung YC, Wu MH, Yang SC, Pan SH, Shih JY, Chan WK, Yang PC (2007) Targeting neuropilin 1 as an antitumor strategy in lung cancer. Clin Cancer Res 13(16):4759-4768. doi: 10.1158/1078-0432.CCR-07-0001
146. Berge M, Bonnin P, Sulpice E, Vilar J, Allanic D, Silvestre JS, Levy BI, Tucker GC, Tobelem G, Merkulova-Rainon T (2010) Small interfering RNAs induce target-independent inhibition of tumor growth and vasculature remodeling in a mouse model of hepatocellular carcinoma. Am J Pathol 177(6):3192-3201. doi: 10.2353/ajpath.2010.100157
147. Narazaki M, Segarra M, Tosato G (2008) Neuropilin-2: a new molecular target for antiangiogenic and antitumor strategies. J Natl Cancer Inst 100(2):81-83. doi: 10.1093/jnci/djm305