In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 13 ( 2015-07-01), p. 2619-2628
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-Ihigh) 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-Ihigh melanoma growth in immunocompetent but not in immunodeficient (IFNγ−/−, 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. Cancer Res; 75(13); 2619–28. ©2015 AACR.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/0008-5472.CAN-14-2524
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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