title: IRX-2, a novel biologic, favors the expansion of T effector over T regulatory cells in a human tumor microenvironment model.
abstract: IRX-2, a natural cytokine biological with multiple components, has been used in preclinical and clinical studies to promote antitumor activity of T lymphocytes. To define cellular mechanisms responsible for antitumor effects of IRX-2, its ability to induce effector T cells (Teff) was examined in a model simulating the tumor microenvironment. An in vitro model containing conventional CD4(+)CD25(-) cells co-cultured with autologous immature dendritic cells, irradiated tumor cells, and cytokines was used to study differentiation and expansion of regulatory T cells (Treg) and Teff in the presence and absence of IRX-2. Phenotype, suppressor function, signaling, and cytokine production were serially measured using flow cytometry, Western blots, CFSE-based suppressor assays, and Luminex-based analyses. The presence of IRX-2 in the co-cultures promoted the induction and expansion of IFN-γ(+)Tbet(+) Teff and significantly (p < 0.01) decreased the induction of inducible IL-10(+)TGF-β(+) Treg. The responsible mechanism involved IFN-γ-driven T cell polarization towards Teff and suppression of Treg differentiation. In an in vitro model simulating the human tumor microenvironment, IRX-2 promoted Teff expansion and antitumor activity without inducing Treg. Thus, IRX-2 could be considered as a promising component of future antitumor therapies.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Bastian
authors.initials: B
authors.lastname: Schilling
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Harasymczuk
authors.forename: Patrick
authors.initials: P
authors.lastname: Schuler
authors.forename: James E
authors.initials: JE
authors.lastname: Egan
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D016207:Cytokines / Q000494:pharmacology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D016207:Cytokines; C114857:IRX 2; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma