Plasticity of Type I Interferon-Mediated Responses in Cancer Therapy: From Anti-tumor Immunity to Resistance

Abstract

The efficacy of several therapeutic strategies against cancer, including cytotoxic drugs, radiotherapy, targeted immunotherapies and oncolytic viruses, depend on intact type I interferon (IFN) signaling for the promotion of both direct (tumor cell inhibition) and indirect (anti-tumor immune responses) effects. Malfunctions of this pathway in tumor cells or in immune cells may be responsible for the lack of response or resistance. Although type I IFN signaling is required to trigger anti-tumor immunity, emerging evidence indicates that chronic activation of type I IFN pathway may be involved in mediating resistance to different cancer treatments. The plastic and dynamic features of type I IFN responses should be carefully considered to fully exploit the therapeutic potential of strategies targeting IFN signaling. Here, we review available evidence supporting the involvement of type I IFN signaling in mediating resistance to various cancer therapies and highlight the most promising modalities that are being tested to overcome resistance.

Keywords: cancer immunotherapy; immune responses; interferons; resistance mechanisms; tumor microenvironment.

Figure 1

Type I IFNs are secreted by infected cells upon recognition of damage associated molecular patterns (DAMPs) and pathogen associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), which include transmembrane Toll-like receptors (TLRs), cyclic GMP-AMP synthase (cGAS), RIG-I like receptors, MDA-5, DDX41, and DAI. Once these sensors have been activated, they interact with adaptor proteins, such as TIR-domain-containing adaptor inducing IFN (TRIF), MyD88 adapter-like (Mal), mitochondrial anti-viral signaling protein (MAVS) or STING. These adapter proteins recruit kinases indirectly or directly, which then phosphorylate IFN regulatory factor 3/7 triggering its translocation into the nucleus, where it binds to the regulatory domains of the IFN-β/α gene promoter. Upon production, type I IFNs signal via a transmembrane receptor composed of IFNAR1 and IFNAR2 subunits. Canonically, upon binding to IFN, IFNAR phosphorylates and activates the receptor-associated Janus kinase 1 (JAK1) and tyrosine kinases 2 (Tyk2), which subsequently lead to the phosphorylation of signal transducer and activator of transduction 1 and 2 (STAT1 and STAT2) present in the cytosol. Upon activation, these proteins dimerize, get translocated to the nucleus and bind to IRF9 to form a STAT1-STAT2-IRF9 complex (ISGF3). This complex then binds to IFN stimulated response elements (ISRE) in the promoter region of IFN-stimulated genes (ISG), leading to the activation of ISG transcription, most of which contribute to immune-stimulatory and anti-viral effects. Some of the ISGs provide feedback inhibition of type I IFN signaling. Non-canonical pathways of type I IFN signaling can be mediated by STAT homodimers or unphosphorylated STAT1-STAT2 heterodimers leading to the formation of unphosphorylated ISGF3 (U-ISGF3). U-ISGF3 maintains the subset of ISGs whose production leads to DNA damage resistance. SOCS proteins produced on binding of phosphorylated STAT3 homodimers to GAS promoter are involved in providing negative regulation to type I IFN signaling.