Complete response to high-dose IL-2 and enhanced IFN(+)Th17:T-REG ratio in a melanoma patient

• Type of Material: Article
• Authors: Maggie L. Diller, Emory University; Ragini R. Kudchadkar, Emory University; Keith A Delman, Emory University; David H Lawson, Emory University; Mandy L Ford, Emory University
• Language: English
• Date: 2016-10-01
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Wolters Kluwer Health, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1097/CMR.0000000000000283
• Title of Journal or Parent Work: Melanoma Research
• ISSN: 0960-8931
• Volume: 26
• Issue: 5
• Start Page: 535
• End Page: 539
• Grant/Funding Information: Additional support was provided by an anonymous donor to establish the Surgical Oncology/ Medical Research Fellow Fund within the Division of Surgical Oncology in the Emory School of Medicine Department of Surgery; This work was supported by the Kennedy Seed Grant, the Winship Skin Cancer and Melanoma Fund, and NIH GM104323.
• Keywords: T-CELLS; BLOCKADE; Dermatology; Oncology; IMMUNOTHERAPY; Research & Experimental Medicine; INTERLEUKIN-2; Th17 cells; IFN(+)Th17 cells; TUMOR-GROWTH; Medicine, Research & Experimental; EXPRESSION; CANCER; Th17:T-REG ratio; Science & Technology; Life Sciences & Biomedicine; melanoma; IFN-GAMMA; ENDOGENOUS IL-17; METASTATIC MELANOMA; high-dose IL-2
• Research Categories: Health Sciences, Oncology

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 TREGson 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 IFNγ+Th17 cells in the complete responder compared with all nonresponders. As such, the complete responder showed a high IFNγ+Th17 : TREG ratio. Our results suggest that a distinct immunophenotype may be associated with response to HDIL-2. The peripheral IFNγ+Th17 : 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.