title: Complete response to high-dose IL-2 and enhanced IFNγ+Th17 :  TREG ratio in a melanoma patient.
abstract: High-dose IL-2 (HDIL-2) is associated with complete and durable responses in only 5-10% of patients with stage intravenous melanoma and the toxicity profile is significant. In-vivo human models have recently shown a stimulatory effect of exogenous IL-2 on both the Th17 and regulatory T-cell (TREG) compartments. We investigated and compared the effect of HDIL-2 on the Th17 and TREG compartments in HDIL-2 responders versus nonresponders. HDIL-2 was administered at a dose of 720 000 IU/kg to patients with melanoma (n=6) and peripheral blood was collected at baseline and at 24, 48, 72, and 96 h during treatment. Peripheral blood mononuclear cells were isolated and subjected to intracellular cytokine and extracellular receptor staining for flow cytometry. Five of six patients progressed clinically on HDIL-2 therapy, and these patients showed an increase in the frequency of TREGs on day 4 of treatment. A single patient responded to HDIL-2 therapy and showed a decrease in the frequency of TREG cells on day 4 of treatment. We found that HDIL-2 resulted in a larger increase in the frequency and total numbers of IFNγTh17 cells in the complete responder compared with all nonresponders. As such, the complete responder showed a high IFNγTh17 : TREG ratio. Our results suggest that a distinct immunophenotype may be associated with response to HDIL-2. The peripheral IFNγTh17 : TREG ratio may serve as an early biomarker in the setting of HDIL-2 to help identify those patients who would benefit from subsequent cycles.
authors.affiliation: aEmory University Department of Surgery bEmory University Winship Cancer Institute cEmory Transplant Center, Atlanta, Georgia, USA.
authors.forename: Maggie L
authors.initials: ML
authors.lastname: Diller
authors.forename: Ragini R
authors.initials: RR
authors.lastname: Kudchadkar
authors.forename: Keith A
authors.initials: KA
authors.lastname: Delman
authors.forename: David H
authors.initials: DH
authors.lastname: Lawson
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ford
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism*; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D058504:Th17 Cells / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D010446:Peptide Fragments; C069261:interferon gamma (1-39); D007371:Interferon-gamma