TNFR2 blockade alone or in combination with PD-1 blockade shows therapeutic efficacy in murine cancer models

J Leukoc Biol. 2020 Jun;107(6):981-991. doi: 10.1002/JLB.5MA0420-375RRRRR. Epub 2020 May 24.


Immune checkpoint inhibitors are profoundly transforming cancer therapy, but response rates vary widely. The efficacy of checkpoint inhibitors, such as anti-programmed death receptor-1 (anti-PD-1), might be increased by combination therapies. TNFR2 has emerged as a new target due to its massive expression on highly immunosuppressive regulatory T cells (Tregs) in the microenvironment and on certain tumor cells. In murine colon cancer models CT26 and MC38, we evaluated the efficacy of a new anti-TNFR2 antibody alone or in combination with anti-PD-1 therapy. Tumor-bearing mice were treated with placebo, anti-PD-1 alone, anti-TNFR2 alone, or combination anti-PD-1 and anti-TNFR2. We found that combination therapy had the greatest efficacy by complete tumor regression and elimination (cure) in 65-70% of animals. The next most effective therapy was anti-TNFR2 alone (20-50% cured), whereas the least effective was anti-PD-1 alone (10-25% cured). The mode of action, according to in vivo and in vitro methods including FACS analysis, was by killing immunosuppressive Tregs in the tumor microenvironment and increasing the ratio of CD8+ T effectors (Teffs) to Tregs. We also found that sequence of antibody delivery altered outcome. The two most effective sequences were simultaneous delivery (70% cured) followed by anti-TNFR2 preceding anti-PD-1 (40% cured), and the least effective was by anti-PD-1 preceding anti-TNFR2 (10% cured). We conclude that anti-PD-1 is best enhanced by simultaneous administration with anti-TNFR2, and anti-TNFR2 alone may be potentially useful strategy for those do not respond to, or cannot tolerate, anti-PD-1 or other checkpoint inhibitors.

Keywords: ADCC; PD-1; TNFR2; Teff; Tregs; antibodies; cancer; checkpoint blockade; combination immunotherapy; immunotherapy; oncology.

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / chemistry
  • Antineoplastic Agents, Immunological / pharmacology*
  • Cell Death / drug effects
  • Cell Death / immunology
  • Cell Line, Tumor
  • Cell Proliferation
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / therapy*
  • Combined Modality Therapy / methods
  • Drug Administration Schedule
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunotherapy / methods
  • Mice
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, Tumor Necrosis Factor, Type II / antagonists & inhibitors*
  • Receptors, Tumor Necrosis Factor, Type II / genetics
  • Receptors, Tumor Necrosis Factor, Type II / immunology
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / pathology
  • Treatment Outcome
  • Tumor Burden / drug effects
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents, Immunological
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Tumor Necrosis Factor, Type II