The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells

Abstract

// Caroline Jochems 1 , Massimo Fantini 1 , Romaine I. Fernando 1 , Anna R. Kwilas 1 , Renee N. Donahue 1 , Lauren M. Lepone 1 , Italia Grenga 1 , Young-Seung Kim 2 , Martin W. Brechbiel 2 , James L. Gulley 3 , Ravi A. Madan 3 , Christopher R. Heery 1 , James W. Hodge 1 , Robert Newton 4 , Jeffrey Schlom 1, * , Kwong Y. Tsang 1, * 1 Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 2 Radioimmune Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 3 Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 4 Incyte Corporation, Wilmington, DE, USA * These authors contributed equally to this work Correspondence to: Jeffrey Schlom, email: js141c@nih.gov Keywords: IDO inhibitor, dendritic cells, T cells, indoleamine-2,3-dioxygenase (IDO), Tregs Received: February 29, 2016      Accepted: April 26, 2016      Published: May 12, 2016 ABSTRACT Epacadostat is a novel inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1) that suppresses systemic tryptophan catabolism and is currently being evaluated in ongoing clinical trials. We investigated the effects of epacadostat on (a) human dendritic cells (DCs) with respect to maturation and ability to activate human tumor antigen-specific cytotoxic T-cell (CTL) lines, and subsequent T-cell lysis of tumor cells, (b) human regulatory T cells (Tregs), and (c) human peripheral blood mononuclear cells (PBMCs) in vitro . Simultaneous treatment with epacadostat and IFN-γ plus lipopolysaccharide (LPS) did not change the phenotype of matured human DCs, and as expected decreased the tryptophan breakdown and kynurenine production. Peptide-specific T-cell lines stimulated with DCs pulsed with peptide produced significantly more IFN-γ, TNFα, GM-CSF and IL-8 if the DCs were treated with epacadostat. These T cells also displayed higher levels of tumor cell lysis on a per cell basis. Epacadostat also significantly decreased Treg proliferation induced by IDO production from IFN-γ plus LPS matured human DCs, although the Treg phenotype did not change. Multicolor flow cytometry was performed on human PBMCs treated with epacadostat; analysis of 123 discrete immune cell subsets revealed no changes in major immune cell types, an increase in activated CD83 + conventional DCs, and a decrease in immature activated Tim3 + NK cells. These studies show for the first time several effects of epacadostat on human DCs, and subsequent effects on CTL and Tregs, and provide a rationale as to how epacadostat could potentially increase the efficacy of immunotherapeutics, including cancer vaccines.