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: Florie Bertrand, Julia Rochotte, Céline Colacios, Anne Montfort, Anne-Françoise Tilkin-Mariamé, Christian Touriol, Philippe Rochaix, Isabelle Lajoie-Mazenc, Nathalie Andrieu-Abadie, Thierry Levade, Hervé Benoist, Bruno Ségui
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 13 Pg. 2619-28 (Jul 01 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25977337 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Receptors, Tumor Necrosis Factor, Type I
• Tumor Necrosis Factor-alpha

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Lymphocytes, Tumor-Infiltrating (immunology)
• Melanoma, Experimental (immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Receptors, Tumor Necrosis Factor, Type I (deficiency, immunology)
• Tumor Escape (immunology)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, immunology)