Sichuan Huiyang Life-Engineering Co. Ltd.

Purpose: Antiproliferative, antiviral, and immunomodulatory activities of endogenous type I IFNs (IFN1) prompt the design of recombinant IFN1 for therapeutic purposes. However, most of the designed IFNs exhibited suboptimal therapeutic efficacies against solid tumors. Here, we report evaluation of the in vitro and in vivo antitumorigenic activities of a novel recombinant IFN termed sIFN-I.Experimental Design: We compared primary and tertiary structures of sIFN-I with its parental human IFNα-2b, as well as affinities of these ligands for IFN1 receptor chains and pharmacokinetics. These IFN1 species were also compared for their ability to induce JAK–STAT signaling and expression of the IFN1-stimulated genes and to elicit antitumorigenic effects. Effects of sIFN-I on tumor angiogenesis and immune infiltration were also tested in transplanted and genetically engineered immunocompetent mouse models.Results: sIFN-I displayed greater affinity for IFNAR1 (over IFNAR2) chain of the IFN1 receptor and elicited a greater extent of IFN1 signaling and expression of IFN-inducible genes in human cells. Unlike IFNα-2b, sIFN-I induced JAK–STAT signaling in mouse cells and exhibited an extended half-life in mice. Treatment with sIFN-I inhibited intratumoral angiogenesis, increased CD8+ T-cell infiltration, and robustly suppressed growth of transplantable and genetically engineered tumors in immunodeficient and immunocompetent mice.Conclusions: These findings define sIFN-I as a novel recombinant IFN1 with potent preclinical antitumorigenic effects against solid tumor, thereby prompting the assessment of sIFN-I clinical efficacy in humans. Clin Cancer Res; 23(8); 2038–49. ©2016 AACR.

Interferon-related secretome from direct interaction between immune cells and tumor cells is required for upregulation of PD-L1 in tumor cells Dear Editor, PD-L1, also known as CD274, plays a vital role in tumor cell related immune escape.It can be expressed on the cell surface of many solid tumors (Brahmer et al., 2012) and inhibits T cell proliferation and cytokine production by binding to the T cell surface receptor programmed death 1 (PD-1) or B7-1 (McClanahan et al., 2015).In 2013, targeting PD-1/ PD-L1 signaling for cancer immunotherapy was selected as the No.1 scientific breakthrough of the year by the editors of Science.Interferons (IFNs) are a group of pleiotropic cytokines, demonstrated anti-viral, anti-tumor, and immune regulatory functions (York et al., 2015).Type I interferon binds a heterodimeric receptor composed of IFNAR1 and IFNAR2.This activates a canonical JAK/STAT signaling pathway that ultimately induces a set of interferon-stimulated genes to exert its biological activity (Ejlerskov et al., 2015).Recently, PD-L1 was reported to be downstream of IFN signaling in human oral squamous carcinoma, melanoma, and human acute myeloid leukemia blast cells (Chen et al., 2012;Furuta et al., 2014;Kronig et al., 2014).The tumor microenvironment plays an important role in tumor growth and metastasis.Different components of the tumor microenvironment such as T cells, B cells, NK cells, dendritic cells, mast cells, granulocytes, Treg cells, myeloid derived suppressor cells (MDSC), and tumor associated macrophages (TAM) are recruited by different pathways (Joyce and Fearon, 2015).Tumor cells have been shown to upregulate PD-L1 after interacting with infiltrating immune cells (Cho et al., 2011;Hou et al., 2014), but the mechanism by which this occurs is not well understood.In this study, we found that PD-L1 upregulation in tumors was dependent on direct interaction with immune cells and was driven by a secreted factor such as type I interferon after cell-cell contact.Previous studies have demonstrated a positive correlation between tumor-infiltrating immune cells and elevated PD-L1 expression in tumor cells, but the mechanism by