title: Blocking Tumor Necrosis Factor α Enhances CD8 T-cell-Dependent Immunity in Experimental Melanoma.
abstract: TNF plays a dual, still enigmatic role in melanoma, either acting as a cytotoxic cytokine or favoring a tumorigenic inflammatory microenvironment. Herein, the tumor growth of melanoma cell lines expressing major histocompatibility complex class I molecules at high levels (MHC-I(high)) was dramatically impaired in TNF-deficient mice, and this was associated with enhanced tumor-infiltrating CD8(+) T lymphocytes. Immunodepletion of CD8 T cells fully restored melanoma growth in TNF(-/-) mice. Systemic administration of Etanercept inhibited MHC-I(high) melanoma growth in immunocompetent but not in immunodeficient (IFNγ(-/-), nude, or CD8(-/-)) mice. MHC-I(high) melanoma growth was also reduced in mice lacking TNF-R1, but not TNF-R2. TNF(-/-) and TNF-R1(-/-) mice as well as Etanercept-treated WT mice displayed enhanced intratumor content of high endothelial venules surrounded by high CD8(+) T-cell density. Adoptive transfer of activated TNF-R1-deficient or -proficient CD8(+) T cells in CD8-deficient mice bearing B16K1 tumors demonstrated that TNF-R1 deficiency facilitates the accumulation of live CD8(+) T cells into the tumors. Moreover, in vitro experiments indicated that TNF triggered activated CD8(+) T cell death in a TNF-R1-dependent manner, likely limiting the accumulation of tumor-infiltrating CD8(+) T cells in TNF/TNF-R1-proficient animals. Collectively, our observations indicate that TNF-R1-dependent TNF signaling impairs tumor-infiltrating CD8(+) T-cell accumulation and may serve as a putative target to favor CD8(+) T-cell-dependent immune response in melanoma.
authors.affiliation: INSERM UMR 1037, Toulouse, France. Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France.
authors.forename: Florie
authors.initials: F
authors.lastname: Bertrand
authors.affiliation: INSERM UMR 1037, Toulouse, France. Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France. Université Toulouse III - Paul Sabatier, Toulouse, France.
authors.forename: Julia
authors.initials: J
authors.lastname: Rochotte
authors.affiliation: INSERM UMR 1037, Toulouse, France. Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France. Université Toulouse III - Paul Sabatier, Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Colacios
authors.affiliation: INSERM UMR 1037, Toulouse, France. Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Montfort
authors.affiliation: INSERM UMR 1037, Toulouse, France.
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Tilkin-Mariamé
authors.affiliation: INSERM UMR 1037, Toulouse, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Touriol
authors.affiliation: Institut Universitaire du Cancer, Institut Claudius Regaud, Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rochaix
authors.affiliation: INSERM UMR 1037, Toulouse, France. Université Toulouse III - Paul Sabatier, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lajoie-Mazenc
authors.affiliation: INSERM UMR 1037, Toulouse, France. Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Andrieu-Abadie
authors.affiliation: INSERM UMR 1037, Toulouse, France. Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France. Université Toulouse III - Paul Sabatier, Toulouse, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
authors.affiliation: INSERM UMR 1037, Toulouse, France. Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France. Université Toulouse III - Paul Sabatier, Toulouse, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Benoist
authors.affiliation: INSERM UMR 1037, Toulouse, France. Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France. Université Toulouse III - Paul Sabatier, Toulouse, France. bruno.segui@inserm.fr.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ségui
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000276:immunology; D019139:Tumor Escape / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha