title: IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients.
abstract: 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.
authors.forename: Geok Choo
authors.initials: GC
authors.lastname: Sim
authors.forename: Natalia
authors.initials: N
authors.lastname: Martin-Orozco
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Sheng
authors.initials: S
authors.lastname: Wu
authors.forename: Edwina
authors.initials: E
authors.lastname: Washington
authors.forename: Deborah
authors.initials: D
authors.lastname: Sanders
authors.forename: Carol
authors.initials: C
authors.lastname: Lacey
authors.forename: Yijun
authors.initials: Y
authors.lastname: Wang
authors.forename: Luis
authors.initials: L
authors.lastname: Vence
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.forename: Laszlo
authors.initials: L
authors.lastname: Radvanyi
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism*; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000502:physiology*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell