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

• Published in: The Journal of clinical investigation 2014-01, Vol.124 (1), p.99-110
• Main Authors: Sim, Geok Choo, Martin-Orozco, Natalia, Jin, Lei, Yang, Yan, Wu, Sheng, Washington, Edwina, Sanders, Deborah, Lacey, Carol, Wang, Yijun, Vence, Luis, Hwu, Patrick, Radvanyi, Laszlo
• Format: Article
• Language: English
• Subjects: Adult; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Cytokines - metabolism; Female; Humans; Immunosuppression; 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
• ISSN: 0021-9738; 1558-8238
• 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.