IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients

J Clin Invest. 2014 Jan;124(1):99-110. doi: 10.1172/JCI46266.


High-dose (HD) IL-2 therapy in patients with cancer increases the general population of Tregs, which are positive for CD4, CD25, and the Treg-specific marker Foxp3. It is unknown whether specific subsets of Tregs are activated and expanded during HD IL-2 therapy or whether activation of any particular Treg subset correlates with clinical outcome. Here, we evaluated Treg population subsets that were induced in patients with melanoma following HD IL-2 therapy. We identified a Treg population that was positive for CD4, CD25, Foxp3, and the inducible T cell costimulator (ICOS). This Treg population increased more than any other lymphocyte subset during HD IL-2 therapy and had an activated Treg phenotype, as indicated by high levels of CD39, CD73, and TGF-β. ICOS(+) Tregs were the most proliferative lymphocyte population in the blood after IL-2 therapy. Patients with melanoma with enhanced expansion of ICOS(+) Tregs in blood following the first cycle of HD IL-2 therapy had worse clinical outcomes than patients with fewer ICOS(+) Tregs. However, there was no difference in total Treg expansion between HD IL-2 responders and nonresponders. These data suggest that increased expansion of the ICOS(+) Treg population following the first cycle of HD IL-2 therapy may be predictive of clinical outcome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacology
  • Cell Proliferation / drug effects
  • Cytokines / metabolism
  • Female
  • Humans
  • Immunosuppression Therapy
  • Inducible T-Cell Co-Stimulator Protein / metabolism*
  • Interleukin-2 / administration & dosage*
  • Interleukin-2 / pharmacology
  • Lymphocyte Activation
  • Male
  • Melanoma / drug therapy*
  • Melanoma / immunology
  • Middle Aged
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / physiology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / physiology*
  • Treatment Outcome


  • Antineoplastic Agents
  • Cytokines
  • ICOS protein, human
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukin-2
  • Receptors, Antigen, T-Cell