IL2/Anti-IL2 Complex Combined with CTLA-4, But Not PD-1, Blockade Rescues Antitumor NK Cell Function by Regulatory T-cell Modulation

Cancer Immunol Res. 2019 Mar;7(3):443-457. doi: 10.1158/2326-6066.CIR-18-0697. Epub 2019 Jan 16.


High-dose IL2 immunotherapy can induce long-lasting cancer regression but is toxic and insufficiently efficacious. Improvements are obtained with IL2/anti-IL2 complexes (IL2Cx), which redirect IL2 action to CD8+ T and natural killer (NK) cells. Here, we evaluated the efficacy of combining IL2Cx with blockade of inhibitory immune pathways. In an autochthonous lung adenocarcinoma model, we show that the IL2Cx/anti-PD-1 combination increases CD8+ T-cell infiltration of the lung and controls tumor growth. In the B16-OVA model, which is resistant to checkpoint inhibition, combination of IL2Cx with PD-1 or CTLA-4 pathway blockade reverses that resistance. Both combinations work by reinvigorating exhausted intratumoral CD8+ T cells and by increasing the breadth of tumor-specific T-cell responses. However, only the IL2Cx/anti-CTLA-4 combination is able to rescue NK cell antitumor function by modulating intratumoral regulatory T cells. Overall, association of IL2Cx with PD-1 or CTLA-4 pathway blockade acts by different cellular mechanisms, paving the way for the rational design of combinatorial antitumor therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use*
  • Antigen-Antibody Complex / therapeutic use*
  • CD8-Positive T-Lymphocytes / immunology
  • CTLA-4 Antigen / immunology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Immunotherapy
  • Interleukin-2 / immunology*
  • Killer Cells, Natural / immunology*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / therapy
  • Programmed Cell Death 1 Receptor / immunology
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology


  • Antibodies, Monoclonal
  • Antigen-Antibody Complex
  • CTLA-4 Antigen
  • Interleukin-2
  • Programmed Cell Death 1 Receptor