Direct Effects of Type I Interferons on Cells of the Immune System

Abstract

Type I interferons (IFN-I) are well-known inducers of tumor cell apoptosis and antiangiogenesis via signaling through a common receptor interferon alpha receptor (IFNAR). IFNAR induces the Janus activated kinase-signal transducer and activation of transcription (JAK-STAT) pathway in most cells, along with other biochemical pathways that may differentially operate, depending on the responding cell subset, and jointly control a large collection of genes. IFNs-I were found to systemically activate natural killer (NK) cell activity. Recently, mouse experiments have shown that IFNs-I directly activate other cells of the immune system, such as antigen-presenting dendritic cells (DC) and CD4 and CD8 T cells. Signaling through the IFNAR in T cells is critical for the acquisition of effector functions. Cross-talk between IFNAR and the pathways turned on by other surface lymphocyte receptors has been described. Importantly, IFNs-I also increase antigen presentation of the tumor cells to be recognized by T lymphocytes. These IFN-driven immunostimulatory pathways offer opportunities to devise combinatorial immunotherapy strategies. Clin Cancer Res; 17(9); 2619-27. Ó2011 AACR.

Expression of the Immune Regulator Tripartite-Motif 21 Is Controlled by IFN Regulatory Factors

“…The molecular mechanisms regulating Trim21 expression are unknown, but because Trim21 is induced by IFNs we hypothesized that transcription factors activated by IFN signaling control Trim21 expression. Type I IFNs bind to the heterodimeric IFN-a/b receptor (IFNAR), leading to the activation of the JAK-STAT pathway and phosphorylation of STAT1 and STAT2, as well as other STATs (25,26). pSTAT1 and pSTAT2 form a complex with IRF9 (IFN-stimulated gene factor 3 [ISGF3]) that subsequently activates the transcription of IFN-stimulated genes (ISGs) by binding to IFN-stimulated response elements (ISRE) (27)(28)(29).…”

Redirected T-Cell Killing of Solid Cancers Targeted with an Anti-CD3/Trop-2–Bispecific Antibody Is Enhanced in Combination with Interferon-α

“…For some tumors, IFNa can have a direct and potent antiproliferative effect through activation of STAT1 (22). IFNa has a pleiotropic influence on immune responses through effects on myeloid cells, NK cells, DCs, B cells, and T cells, and influences the production of numerous other cytokines, including IFNg, TNFa, IL1, IL6, IL12, IL15, and IL18 (23). Several reports identify CD8 þ T cells as direct targets of IFNa, affecting their IFNg production, survival, activation, clonal expansion, and memory differentiation (24)(25)(26)(27)(28)(29)(30)(31).…”

HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment

“…Tumor-infiltrating lymphocytes may be incompletely activated, anergic, or functionally defective (47). pIC/PPHAffibody led to the induction of IFNa/b and additional cytokines that can activate various cells of the innate system, such as NK, macrophages, and antigen presenting cells, which in turn activate the adaptive immune system (48). Type I IFN can also directly induce the adaptive immune system by regulating T-cell survival, proliferation, and activation (49,50).…”