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

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

Eleonora Aricò et al. Cancers (Basel).

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.

Keywords: cancer; dendritic cells; immunotherapy; type I interferon.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
The major milestones of IFN-I research, here shown in orange, resulted in IFN-α being the first immunotherapeutic drug approved by the FDA, at a time when their mechanisms of action were not fully unraveled. Despite initial enthusiasm, clinical use of IFN-I in cancer has now been largely replaced by novel targeted therapies. The accumulated evidence of the last ten years, enlisted in colors on the right side, suggests a rethinking of the prominent role of IFN-I in determining cancer development, progression, and response to therapy. The importance of IFN-I signaling emerged as crucial for response to chemotherapy, radiotherapy, immune checkpoint inhibitor therapy, and epigenetic drugs (shown in green). Moreover, in vitro and clinical observations (shown in blue) from chronic myeloid leukemia (CML) and, more recently, breast cancer highlighted IFN-I as regulators of cancer stem cell proliferation and differentiation. Lastly, IFN-I emerged as essential for the ability of dendritic cells (DC) to activate antitumor immunity (in yellow).
Figure 2
Figure 2
IFN-I exerts an inhibitory effect on growth and persistence of CSC. (Left) basal levels of endogenous IFN-I produced by either cancer cells and/or tumor infiltrating immune cells control Cancer Stem Cells (CSC) proliferation and differentiation (as demonstrated in CML and breast cancer). (Center) disruption of IFN-I signaling leads to the increased proliferation and migration of CSC. (Right) low-dose exogenous IFN-I administration can have a double effect on CSC by favoring differentiation over self-renewal and activating immune response against CSC.
Figure 3
Figure 3
IFN-DC for in situ vaccination. The balance between immune activating vs. immunosuppressive cells/signals affects the antitumor function of immune effector cells. In immunosuppressed tumors (left), myeloid derived suppressor cells (MDSC), and regulatory T cells (Treg) overcome immune activating signals released by tumor infiltrating DC, by both direct inhibitory signals and secreted cytokines (e.g., IL-10), eventually resulting in reduced antitumor activity of both the effector T cells and NK cells. (Right) in situ vaccination with ex vivo generated IFN-DC (top), combined with immunogenic cell death (ICD) inducers to ensure the release of tumor antigens, stimulates DC cross-presentation and tumor-specific T cells generation. Additionally, IFN-DC can overrun immunosuppressive cells and signals by secreting a high amount of immune activating cytokine IL-12 and T cell attracting chemokines (CXCL9 and CXCL10), thus subverting the tumor microenvironment into a more inflamed and immune active one.
Figure 4
Figure 4
The conclusion. The tumor microenvironment (TME) is characterized by an extremely high inter and intra-tumor heterogeneity (top), with tumors showing different levels and forms of immune cell infiltration. The extent of endogenous IFN-I signaling activation plays a key role in regulating quantity and quality of immune cell infiltrate and, as a consequence, tumor PD-L1 expression levels. Absence of IFN-I signaling is typical of non-infiltrated tumors (left). Insufficient levels of IFN-I signaling are usually associated with immunosuppressed TME with a high infiltration of MDSC and Treg and low percentages of antitumor T cells. Tumors with intact IFN-I signaling are commonly inflamed with antitumor T cells that can be inhibited by the expression of immune checkpoints (center), whereas excessive IFN-I signaling activation is often observed in tumors with exhausted antitumor T cells and activation of immunosuppressive mechanisms (right). In light of such heterogeneity, efficacy of current therapies (middle) varies depending on tumor status and TME features. In settings with absent or reduced IFN-I signaling, chemotherapy, radiotherapy, and epigenetic drugs can modify TME by reactivating IFN-I signaling, thus resulting in the induction of antitumor response and/or decreased immunosuppression. In case IFN-I signaling is active in TME, ICI can exert its maximum potentials. (Bottom) potential windows of action for renewed use of IFN-I (either directly or indirectly) are hypothesized. Exogenous IFN-I or endogenous IFN-I inducers can be timely combined with anti-tumor cytotoxic therapies to induce antitumor immunity or overcome tumor-induced immune suppression. In the case of non-infiltrated tumors, chemotherapy or radiotherapy can induce ICD, thus releasing tumor antigens, which in the context of endogenous-induced or exogenous administered IFN-I can potentiate anti-tumor immune responses. In tumor-induced immunosuppressed TME, activation of IFN-I signaling can reverse immunosuppression. In both cases, IFN-DC-based in situ vaccination can be envisaged to stimulate antitumor immunity or overcome immunosuppression.

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