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Interferons α and β in cancer: therapeutic opportunities from new insights

Abstract

Over the past decade, preclinical and clinical research have confirmed the essential role of interferons for effective host immunological responses to malignant cells. Type I interferons (IFNα and IFNβ) directly regulate transcription of >100 downstream genes, which results in a myriad of direct (on cancer cells) and indirect (through immune effector cells and vasculature) effects on the tumour. New insights into endogenous and exogenous activation of type I interferons in the tumour and its microenvironment have given impetus to drug discovery and patient evaluation of interferon-directed strategies. When combined with prior observations or with other effective modalities for cancer treatment, modulation of the interferon system could contribute to further reductions in cancer morbidity and mortality. This Review discusses new interferon-directed therapeutic opportunities, ranging from cyclic dinucleotides to genome methylation inhibitors, angiogenesis inhibitors, chemoradiation, complexes with neoantigen-targeted monoclonal antibodies, combinations with other emerging therapeutic interventions and associations of interferon-stimulated gene expression with patient prognosis — all of which are strategies that have or will soon enter translational clinical evaluation.

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Fig. 1: Key events in the clinical development of interferons2,3,4,5,6,129,242,243,244.
Fig. 2: Induction and actions of IFNα and IFNβ.

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Acknowledgements

Instrumental to completion of this commentary were constructive suggestions from critical readings by colleagues G. Stark, R. Silverman, H. J. Cheon, P. Sondel and M. Mastrangelo. K. Kraus provided crucial editorial assistance, as did R. Gordon in his initial preparation of figure 2. For purposes of summation, reference has sometimes been made to reviews (usually those from laboratories in which the seminal discoveries originated), but this has thus occasionally led to omission of complementary publications — to whose authors the author of this Review apologizes. External support over the years to the author’s laboratory from the American Cancer Society, the National Institutes of Health and the Comprehensive Cancer Centers of the US National Cancer Institute at the University of Wisconsin and Cleveland Clinic/Case Western Reserve University contributed to the author’s insights, as did many institutional colleagues at the latter clinical research centers who also had critical roles in helping identify improvements in outcomes for patients with cancer.

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Related links

Interferome: the database of Interferon Regulated Genes: http://www.interferome.org

Glossary

Polyriboinosinic: polyribocytidylic acid

(Poly(I:C)). A double-stranded RNA with one strand being a homopolymer of inosinic acid and the other being a homopolymer of cytidylic acid, with lengths of 0.2–8.0 kb.

Abscopal

An effect in cancer therapy in which the treatment of a localized site results in regression of tumour(s) at distant sites (derived from ab scopus, which means away from target).

Immunoscore

A prognostic immunoprofiling based upon immune cell infiltrates and/or functional activities that can be beneficial for prediction of patient outcome; the tool was pioneered by Jerome Galon and refined by international collaborations.

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Borden, E.C. Interferons α and β in cancer: therapeutic opportunities from new insights. Nat Rev Drug Discov 18, 219–234 (2019). https://doi.org/10.1038/s41573-018-0011-2

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