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Cancer Res. 2015 Jul 1;75(13):2619-28. doi: 10.1158/0008-5472.CAN-14-2524. Epub 2015 May 14.

Blocking Tumor Necrosis Factor α Enhances CD8 T-cell-Dependent Immunity in Experimental Melanoma.

Author information

1
INSERM UMR 1037, Toulouse, France. Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France.
2
INSERM UMR 1037, Toulouse, France. Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France. Université Toulouse III - Paul Sabatier, Toulouse, France.
3
INSERM UMR 1037, Toulouse, France.
4
Institut Universitaire du Cancer, Institut Claudius Regaud, Toulouse, France.
5
INSERM UMR 1037, Toulouse, France. Université Toulouse III - Paul Sabatier, Toulouse, France.
6
INSERM UMR 1037, Toulouse, France. Equipe Labellisée Ligue Contre Le Cancer, Toulouse, France. Université Toulouse III - Paul Sabatier, Toulouse, France. bruno.segui@inserm.fr.

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.

PMID:
25977337
DOI:
10.1158/0008-5472.CAN-14-2524
[Indexed for MEDLINE]
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