TNFα Blockade Overcomes Resistance to anti-PD-1 in Experimental Melanoma

Nat Commun. 2017 Dec 22;8(1):2256. doi: 10.1038/s41467-017-02358-7.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use
  • Antineoplastic Agents, Immunological / pharmacology*
  • Antineoplastic Agents, Immunological / therapeutic use
  • B7-H1 Antigen / drug effects
  • B7-H1 Antigen / metabolism
  • CD8-Positive T-Lymphocytes / drug effects
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Synergism
  • Female
  • Hepatitis A Virus Cellular Receptor 2 / drug effects
  • Hepatitis A Virus Cellular Receptor 2 / metabolism
  • Humans
  • Ipilimumab / therapeutic use
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Mammary Neoplasms, Animal / genetics
  • Mammary Neoplasms, Animal / metabolism
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / metabolism
  • Mice
  • Nivolumab
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • CD274 protein, human
  • Cd274 protein, mouse
  • HAVCR2 protein, human
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Ipilimumab
  • Programmed Cell Death 1 Receptor
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • Nivolumab