Abstract
Antibodies against programmed cell death-1 (PD-1) have considerably changed the treatment for melanoma. However, many patients do not display therapeutic response or eventually relapse. Moreover, patients treated with anti-PD-1 develop immune-related adverse events that can be cured with anti-tumor necrosis factor α (TNF) antibodies. Whether anti-TNF antibodies affect the anti-cancer immune response remains unknown. Our recent work has highlighted that TNFR1-dependent TNF signalling impairs the accumulation of CD8+ tumor-infiltrating T lymphocytes (CD8+ TILs) in mouse melanoma. Herein, our results indicate that TNF or TNFR1 blockade synergizes with anti-PD-1 on anti-cancer immune responses towards solid cancers. Mechanistically, TNF blockade prevents anti-PD-1-induced TIL cell death as well as PD-L1 and TIM-3 expression. TNF expression positively correlates with expression of PD-L1 and TIM-3 in human melanoma specimens. This study provides a strong rationale to develop a combination therapy based on the use of anti-PD-1 and anti-TNF in cancer patients.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / therapeutic use
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Antineoplastic Agents, Immunological / pharmacology*
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Antineoplastic Agents, Immunological / therapeutic use
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B7-H1 Antigen / drug effects
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B7-H1 Antigen / metabolism
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CD8-Positive T-Lymphocytes / drug effects
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Cell Line, Tumor
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Drug Resistance, Neoplasm / drug effects*
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Drug Synergism
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Female
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Hepatitis A Virus Cellular Receptor 2 / drug effects
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Hepatitis A Virus Cellular Receptor 2 / metabolism
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Humans
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Ipilimumab / therapeutic use
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Lymphocytes, Tumor-Infiltrating / drug effects
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Mammary Neoplasms, Animal / genetics
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Mammary Neoplasms, Animal / metabolism
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Melanoma / genetics
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Melanoma / metabolism
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Melanoma, Experimental / drug therapy*
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Melanoma, Experimental / genetics
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Melanoma, Experimental / metabolism
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Mice
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Nivolumab
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Programmed Cell Death 1 Receptor / antagonists & inhibitors*
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Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors*
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Skin Neoplasms / genetics
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Skin Neoplasms / metabolism
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Antibodies, Monoclonal
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Antineoplastic Agents, Immunological
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B7-H1 Antigen
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CD274 protein, human
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Cd274 protein, mouse
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HAVCR2 protein, human
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Havcr2 protein, mouse
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Hepatitis A Virus Cellular Receptor 2
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Ipilimumab
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Programmed Cell Death 1 Receptor
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Receptors, Tumor Necrosis Factor, Type I
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Tumor Necrosis Factor-alpha
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Nivolumab