Blocking Tumor Necrosis Factor α Enhances CD8 T-cell–Dependent Immunity in Experimental Melanoma
Published version of a preprint
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.
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Other published reports showed evidence in mouse models that anti-TNF-a enhances the antitumor activity of combined anti-PD-1 and anti-CTLA-4 immunotherapy, reinforces both CD8 T-cell-dependent immunity and anti-PD-1 therapy, by preventing anti-PD-1-induced cell death of tumor infiltrating lymphocytes as well as PD-L1 and Tim-3 expression.
“Contrarily, other published reports showed evidence in mouse models that anti-TNF-a enhances the antitumor activity of combined anti-PD-1 and anti-CTLA-4 immunotherapy, 61 reinforces both CD8 T-cell-dependent immunity and anti-PD-1 therapy, by preventing anti-PD-1-induced cell death of tumor infiltrating lymphocytes as well as PD-L1 and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3)”
From Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: Review of the literature and personalized risk-based prevention strategy (2020) · cites this paper as [63]
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- Authors
- Bertrand, F., Rochotte, J., Colacios, C., Montfort, A., Tilkin-Mariamé, A.-F., Touriol, C., Rochaix, P., Lajoie-Mazenc, I., Andrieu-Abadie, N., Levade, T., Benoist, H., & Ségui, B.
- Affiliations
- Inserm (FR)
- Université Toulouse III - Paul Sabatier (FR)
- 1INSERM UMR 1037, Toulouse, France.
- Institut Claudius Regaud (FR)
- ORCID
- Venue
- Cancer Research
- Published
- 2015-06-30
- Volume
- 75
- Issue
- 13
- Pages
- 2619-2628
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2146073081
- Cited by
- 113
- References
- 50
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 11 · 2023: 14 · 2022: 14 · 2021: 15 · 2020: 13 · 2019: 5 · 2018: 7 · 2017: 5 · 2016: 7 · 2015: 3
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- TNF-α, TNF receptor 1, melanoma, CD8+ T cells, tumor-infiltrating lymphocytes, etanercept, MHC class I, tumor microenvironment, T cell death, adoptive T cell therapy, high endothelial venules, TNF signaling
- MeSH terms
- Animals, Melanoma, Experimental, Mice, Inbred C57BL, Tumor Necrosis Factor-alpha, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Tumor Escape, Cell Line, Tumor, Receptors, Tumor Necrosis Factor, Type I, Mice
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