Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 124, Issue 1, Pages 99-110Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI46266
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Funding
- Therapeutics and Diagnostics and Novartis [CPRL002AUS08/10PLK02]
- NCI for their Melanoma SPORE Developmental Grant [5 P50 CA093459-05-DRP14]
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- NCI [5P30 CA016672 31]
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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-beta. 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.
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