title: Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth.
abstract: Infiltration of Foxp3(+) regulatory T (T reg) cells is considered to be a critical step during tumor development and progression. T reg cells supposedly suppress locally an effective anti-tumor immune response within tumor tissues, although the precise mechanism by which T reg cells infiltrate the tumor is still unclear. We provide evidence that Neuropilin 1 (Nrp-1), highly expressed by Foxp3(+) T reg cells, regulates the immunological anti-tumor control by guiding T reg cells into the tumor in response to tumor-derived vascular endothelial growth factor (VEGF). We demonstrate for the first time that T cell-specific ablation of Nrp-1 expression results in a significant breakdown in tumor immune escape in various transplantation models and in a spontaneous, endogenously driven melanoma model associated with strongly reduced tumor growth and prolonged tumor-free survival. Strikingly, numbers of tumor-infiltrating Foxp3(+) T reg cells were significantly reduced accompanied by enhanced activation of CD8(+) T cells within tumors of T cell-specific Nrp-1-deficient mice. This phenotype can be reversed by adoptive transfer of Nrp-1(+) T reg cells from wild-type mice. Thus, our data strongly suggest that Nrp-1 acts as a key mediator of Foxp3(+) T reg cell infiltration into the tumor site resulting in a dampened anti-tumor immune response and enhanced tumor progression.
authors.affiliation: Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. wiebke.hansen@uk-essen.de
authors.forename: Wiebke
authors.initials: W
authors.lastname: Hansen
authors.forename: Marina
authors.initials: M
authors.lastname: Hutzler
authors.forename: Simone
authors.initials: S
authors.lastname: Abel
authors.forename: Christina
authors.initials: C
authors.lastname: Alter
authors.forename: Christian
authors.initials: C
authors.lastname: Stockmann
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kliche
authors.forename: Juliane
authors.initials: J
authors.lastname: Albert
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Westendorf
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Jan
authors.initials: J
authors.lastname: Buer
authors.forename: Iris
authors.initials: I
authors.lastname: Helfrich
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D039942:Neuropilin-1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics / Q000276:immunology; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000172:deficiency / Q000235:genetics / Q000276:immunology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1