title: Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors.
abstract: We describe a new mechanism regulating the tumor endothelial barrier and T cell infiltration into tumors. We detected selective expression of the death mediator Fas ligand (FasL, also called CD95L) in the vasculature of human and mouse solid tumors but not in normal vasculature. In these tumors, FasL expression was associated with scarce CD8(+) infiltration and a predominance of FoxP3(+) T regulatory (Treg) cells. Tumor-derived vascular endothelial growth factor A (VEGF-A), interleukin 10 (IL-10) and prostaglandin E2 (PGE2) cooperatively induced FasL expression in endothelial cells, which acquired the ability to kill effector CD8(+) T cells but not Treg cells because of higher levels of c-FLIP expression in Treg cells. In mice, genetic or pharmacologic suppression of FasL produced a substantial increase in the influx of tumor-rejecting CD8(+) over FoxP3(+) T cells. Pharmacologic inhibition of VEGF and PGE2 produced a marked increase in the influx of tumor-rejecting CD8(+) over FoxP3(+) T cells that was dependent on attenuation of FasL expression and led to CD8-dependent tumor growth suppression. Thus, tumor paracrine mechanisms establish a tumor endothelial death barrier, which has a critical role in establishing immune tolerance and determining the fate of tumors.
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Motz
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Santoro
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Wang
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Garrabrant
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ricardo R
authors.initials: RR
authors.lastname: Lastra
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Hagemann
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Priti
authors.initials: P
authors.lastname: Lal
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldman
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Fabian
authors.initials: F
authors.lastname: Benencia
authors.affiliation: 1] Ovarian Cancer Research Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. [2].
authors.forename: George
authors.initials: G
authors.lastname: Coukos
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D004730:Endothelium, Vascular / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007150:Immunohistochemistry; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D009369:Neoplasms / Q000098:blood supply* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology
chemical_list: D000906:Antibodies; C505661:FASLG protein, human; C418974:FOXP3 protein, human; D053222:Fas Ligand Protein; D051858:Forkhead Transcription Factors; D042461:Vascular Endothelial Growth Factor A