Type I Interferons and Cancer: An Evolving Story Demanding Novel Clinical Applications

Abstract

The first report on the antitumor effects of interferon α/β (IFN-I) in mice was published 50 years ago. IFN-α were the first immunotherapeutic drugs approved by the FDA for clinical use in cancer. However, their clinical use occurred at a time when most of their mechanisms of action were still unknown. These cytokines were being used as either conventional cytostatic drugs or non-specific biological response modifiers. Specific biological activities subsequently ascribed to IFN-I were poorly considered for their clinical use. Notably, a lot of the data in humans and mice underlines the importance of endogenous IFN-I, produced by both immune and tumor cells, in the control of tumor growth and in the response to antitumor therapies. While many oncologists consider IFN-I as “dead drugs”, recent studies reveal new mechanisms of action with potential implications in cancer control and immunotherapy response or resistance, suggesting novel rationales for their usage in target and personalized anti-cancer treatments. In this Perspectives Article, we focus on the following aspects: (1) the added value of IFN-I for enhancing the antitumor impact of standard anticancer treatments (chemotherapy and radiotherapy) and new therapeutic approaches, such as check point inhibitors and epigenetic drugs; (2) the role of IFN-I in the control of cancer stem cells growth and its possible implications for the development of novel antitumor therapies; and (3) the role of IFN-I in the development of cancer vaccines and the intriguing therapeutic possibilities offered by in situ delivery of ex vivo IFN-stimulated dendritic cells.

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

“…Alternatively, administration of recombinant type I interferons (IFNs), which have the opposite effect to TGFβ1 [59], may neutralize TGFβ1-mediated induction of N2 TANs. In this context, inducers of immunogenic cell death (ICD), which promote the release of endogenous type I IFNs from tumor cells in situ, may represent the most effective strategy [136,137].…”

“…Uncertain, but administration of ICD-inducing strategies may be preferable [59,137] Administration of CXCR1/2 antagonists Very promising, undergoing advanced clinical evaluation [138][139][140][141] mAb targeting of MMP-9 Unproven, but may represent an alternative strategy to prevent activation of latent TGFβ1 in the TME [98] Small molecule inhibitors of arginase-1 and IDO to preserve arginine and tryptophan, respectively, in the TME Unproven [144,145] Small molecule antagonists of adenosine A 2A receptors, as well as inhibitors of ATP ectonucleotidases and cyclooxygenases to prevent activation of T cell adenylyl cyclase via production of adenosine and PGE 2, respectively Unproven [146] Monoclonal antibody (mAb); indoleamine-2,3-dioxygenase (IDO).…”

Interferons in the Therapy of Severe Coronavirus Infections: A Critical Analysis and Recollection of a Forgotten Therapeutic Regimen with Interferon Beta

“…During decades of clinical experience with various interferon preparations in numerous diseases clinicians had to learn that very different dosing regimens and routes of administration are required in order to exploit a specific pharmacodynamic activity of a certain interferon preparation in the treatment of a particular disease 14 15 16 17 18 19 20 21 22 23 24 25 26 . High doses of interferons must be applied in order to create high serum levels which are probably essential for treatment focused on antiviral or antiproliferative interferon activities.…”

Are we fully exploiting type I Interferons in today's fight against COVID-19 pandemic?

“…A continuous systemic treatment, somehow inspired by the conventional use of these cytokines in patients with chronic hepatitis C infection and cancer, has been suggested in some of the emerging COVID-19 clinical studies. However, taking into account some critical aspects related to toxicity and refractoriness recently underlined [11,45] and discussed above, we believe this treatment schedule should be discouraged in favor of a discontinuous treatment schedule.…”

“…IFN-I were first discovered more than 60 years ago as antiviral substances produced by influenza virus-infected cells, capable of markedly inhibiting viral replication in target cells [9]. These cytokines were the firsts to be cloned and have been extensively used in patients with some viral diseases [10] and cancer (IFN-α) [11], and in the treatment of relapsing-remitting multiple sclerosis (MS) (IFN-β, [12]). Indeed, IFN-I are pleiotropic factors endowed with multiple activities, including both a broad-spectrum antiviral activity [9,10] and a remarkable antiproliferative and immunoregulatory function [13].…”