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.

Integrated analyses of early responses to radiation in glioblastoma identify new alterations in RNA processing and candidate target genes to improve treatment outcomes

“…activation [49]. On the other hand, chronic activation of type I IFN signaling has been linked to adaptive resistance to therapy in many tumor types [50].…”

Hypoxia induces transcriptional and translational downregulation of the type I interferon (IFN) pathway in multiple cancer cell types

“…All together, these data suggest that the relevance of this hypoxic downregulation of the IFN response is the potential effect on enhancing tumour growth by decreasing the cytotoxicity of T lymphocytes and the capacity of dendritic cells (DCs) to process and present antigens (11). As a result, this downregulation could contribute to the radio- and chemo-resistance observed in hypoxic areas as these therapies rely on intact type I IFN signalling (14). This provides a further rational for targeting the hypoxic tumour population in combination with check point inhibitor therapy (45) and selection of hypoxic patients for study of IFN response inducers is warranted.…”

“…Type I IFN is involved in the success of current anticancer treatments both directly (tumour cell inhibition) and indirectly (anti-tumour immune responses to the nucleic acids and proteins released by dying cells, recently named immunogenic cell death, ICD) (14) (9). In mouse models, IFNAR1 neutralization using antibodies blocked the therapeutic effect of antibodies against human epidermal growth factor receptor 2 (HER2) or epidermal growth factor receptor (EGFR) (15, 16).…”

The potential of the combined use of targeted type I interferon pathway inhibitors and oncolytic viruses to treat sarcomas

“…In an alternative type I IFN pathway, STAT homodimers or STAT5 complexed with chicken tumour virus number 10 (CT10) regulator of kinase ligand (CrkL) bind gamma‐activated sequences (GASs), which causes the production of suppressor of cytokine signalling (SOCS) proteins . This alternative type I IFN pathway is believed to increase cell proliferation and promote tumour invasion, metastasis and angiogenesis of various tumour types .…”

“…There are several pharmaceutical options that can be used to augment proteins. 53 This alternative type I IFN pathway is believed to increase cell proliferation and promote tumour invasion, metastasis and angiogenesis of various tumour types. 54 Increased levels of phosphorylated STAT3 homodimers have been detected in some human osteosarcoma, rhabdomyosarcoma, and STS cells.…”