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

被引:81
作者
Bertrand, Florie [1 ,2 ]
Rochotte, Julia [1 ,2 ,3 ]
Colacios, Celine [1 ,2 ,3 ]
Montfort, Anne [1 ,2 ]
Tilkin-Mariame, Anne-Francoise [1 ]
Touriol, Christian [1 ]
Rochaix, Philippe [4 ]
Lajoie-Mazenc, Isabelle [1 ,3 ]
Andrieu-Abadie, Nathalie [1 ,2 ]
Levade, Thierry [1 ,2 ,3 ]
Benoist, Herve [1 ,2 ,3 ]
Segui, Bruno [1 ,2 ,3 ]
机构
[1] INSERM, UMR 1037, F-31037 Toulouse, France
[2] Equipe Labellisee Ligue Contre Canc, Toulouse, France
[3] Univ Toulouse 3, F-31062 Toulouse, France
[4] Inst Univ Canc, Inst Claudius Regaud, Toulouse, France
关键词
HIGH ENDOTHELIAL VENULES; TNF-ALPHA; CHRONIC INFLAMMATION; SUPPRESSOR-CELLS; REGULATORY-CELLS; METASTATIC MELANOMA; MYELOID CELLS; CANCER; MODEL; MICE;
D O I
10.1158/0008-5472.CAN-14-2524
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 (IFN gamma(-/-), nude, or CD8(-/-)) mice. MHC-Ihigh 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. (C) 2015 AACR.
引用
收藏
页码:2619 / 2628
页数:10
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