Exogenous IL-2 Induces FoxP3(+) Th17 Cells In Vivo in Melanoma Patients

• Type of Material: Article
• Authors: Maggie L. Diller, Emory University; Ragini Kudchadkar, Emory University; Keith Delman, Emory University; David Lawson, Emory University; Mandy Ford, Emory University
• Language: English
• Date: 2016-11-01
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Wolters Kluwer Health, Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1097/CJI.0000000000000139
• Title of Journal or Parent Work: Journal of Immunotherapy
• ISSN: 1524-9557
• Volume: 39
• Issue: 9
• Start Page: 355
• End Page: 366
• Grant/Funding Information: This work was supported by the Kennedy Seed Grant, the Winship Skin Cancer and Melanoma Fund, and NIH/NIGMS GM104323 (to MLF).; 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.
• Keywords: Oncology; LARGE ESTABLISHED MELANOMA; IL-6 (+) monocytes; Medicine, Research & Experimental; Immunology; Life Sciences & Biomedicine; T(H)17 CELLS; REGULATORY T-CELLS; Research & Experimental Medicine; TGF-BETA; DIFFERENTIATION; Th17 cells; Science & Technology; MALIGNANT-MELANOMA; GROWTH-FACTOR-BETA; FoxP3 (+) Th17 cells; EFFECTOR FUNCTIONS; HELPER-CELLS; high-dose IL-2 (HDIL-2); CUTTING EDGE; melanoma
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

Th17 cells represent a distinct subset of CD4 + effector T cells with potent pathogenic qualities, capable of directly mediating tumor cell destruction. IL-2 has frequently been shown to have a negative effect on Th17 differentiation while supporting regulatory T-cell (FoxP3 + CD4 + , T REG ) growth and development in both in vitro models and in vivo animal models. We investigated the effect of in vivo IL-2 on both the Th17 and FoxP3 + CD4 + T-cell compartments in a human model of cancer. High-dose IL-2 (HDIL-2) was administered at a dose of 720,000 IU/kg to patients with melanoma (n=7) and peripheral blood was collected at baseline and at 24, 48, 72, and 96 hours posttreatment. Peripheral blood mononuclear cells (PBMCs) were isolated and subjected to intracellular cytokine and extracellular receptor staining for flow cytometry. We report that HDIL-2 increased both frequencies and absolute numbers of Th17 cells on day 4 of treatment. The administration of HDIL-2 to patients with melanoma increased IL- 6 production by peripheral immune cells, a cytokine vital in the downregulation of FoxP3 expression and expansion of the Th17- cell population. Furthermore, we demonstrated that FoxP3 + CD4 + T cells express IL-17 in patients with melanoma undergoing HDIL-2 therapy. Taken together, our findings indicate that HDIL- 2 combined with the conditions of malignancy create an immune environment supportive of Th17 differentiation and that expansion of this compartment may occur through the transdifferentiation of IL-17-secreting FoxP3 + CD4 + T cells.