title: The Potentiation of IFN-γ and Induction of Cytotoxic Proteins by Pegylated IL-10 in Human CD8 T Cells.
abstract: Interleukin-10 (IL-10) exerts both immunosuppressive and immunostimulatory effects. While the immunosuppressive effects are widely known, it has only been recently reported that pegylated recombinant human IL-10 (PEG-rHuIL-10) elicits potent interferon-γ (IFN-γ) and CD8 T-cell-dependent antitumor effects in murine tumor models. In this study, we show that PEG-rHuIL-10 exerts immune inhibitory effects on human peripheral blood mononuclear cell (PBMC) bulk cultures and stimulatory effects in CD8 T cells within the same culture. Also, in isolated CD8 T cells, PEG-rHuIL-10 potentiates prototypic Tc1 cytokine IFN-γ expression and induces perforin and granzyme B secretion. IFN-γ and granzyme B secretion is dependent on T-cell receptor ligation and is therefore not indiscriminately released by PEG-rHuIL-10 treatment. STAT3, NF-κB, AP1, and MEK inhibition blocks IFN-γ potentiation, while perforin induction is impeded by AP1 inhibition, and granzyme B induction is blocked by both AP1 and MEK inhibition. These results extend previous pegylated IL-10 preclinical findings to human CD8 T cells and implicate a strong degree of translation for pegylated IL-10 use in cancer therapy.
authors: ARMO BioSciences, Inc. , Redwood City, California.
authors: Ivan Ho
authors: IH
authors: Chan
authors: ARMO BioSciences, Inc. , Redwood City, California.
authors: Victoria
authors: V
authors: Wu
authors: ARMO BioSciences, Inc. , Redwood City, California.
authors: Melissa
authors: M
authors: Bilardello
authors: ARMO BioSciences, Inc. , Redwood City, California.
authors: Elliot
authors: E
authors: Mar
authors: ARMO BioSciences, Inc. , Redwood City, California.
authors: Martin
authors: M
authors: Oft
authors: ARMO BioSciences, Inc. , Redwood City, California.
authors: Peter
authors: P
authors: Van Vlasselaer
authors: ARMO BioSciences, Inc. , Redwood City, California.
authors: John Brian
authors: JB
authors: Mumm
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000502:physiology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000494:pharmacology*; D054353:Perforin / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D054353:Perforin; D016753:Interleukin-10; D007371:Interferon-gamma; D053804:Granzymes