The Yin and Yang of Type I IFNs in Cancer Promotion and Immune Activation

Abstract

Type I Interferons (IFNs) are key regulators of natural and therapy-induced host defense against viral infection and cancer. Several years of remarkable progress in the field of oncoimmunology have revealed the dual nature of these cytokines. Hence, Type I IFNs may trigger anti-tumoral responses, while leading immune dysfunction and disease progression. This dichotomy relies on the duration and intensity of the transduced signaling, the nature of the unleashed IFN stimulated genes, and the subset of responding cells. Here, we discuss the role of Type I IFNs in the evolving relationship between the host immune system and cancer, as we offer a view of the therapeutic strategies that exploit and require an intact Type I IFN signaling, and the role of these cytokines in inducing adaptive resistance. A deep understanding of the complex, yet highly regulated, network of Type I IFN triggered molecular pathways will help find a timely and immune“logical” way to exploit these cytokines for anticancer therapy.

Targeted Modulation of Interferon Response-Related Genes with IFN-Alpha/Lambda Inhibition

“…Since p53 is known to be involved in the regulation of epigenetic silencing of endogenous retroelements, p53 KO mice may be characterized by a lack of epigenetic integrity and the development of inflammation through the IFN response [32]. Moreover, due to the demonstrated pro-cancer activity of type I IFN following radiation via CD8+ T cell-mediated cytotoxicity protection [41], as well as recent evidence demonstrating that prolonged exposure to type I IFN leads to immune exhaustion allowing cancer cells to escape immune cell surveillance [42,43], we may assume that the previously demonstrated anti-cancer effect of ALOS4 [29,31] in the absence of any cytotoxicity (Figure 1H) is elicited by the inhibition of IFN types I and III. Hence, we propose further investigation of the hypothesis that ALOS4 indirectly influences epigenetic mechanisms and thus modulates IFN types I and III signaling in response to the inflammatory response.…”

Ongoing Replication Stress Response and New Clonal T Cell Development Discriminate Between Liver and Lung Recurrence Sites and Patient Outcomes in Pancreatic Ductal Adenocarcinoma

“…Conversely, patients live longer if their PDAC tumors have low pORG scores (Figure 2C), particularly if they harbor a DDR gene mutation (Figure 3E) and likely fail to productively respond to replication stress caused by DDR defects. A high pORG signature and ongoing response to replication stress was also associated with chronic interferon signaling, which unlike an acute type 1 interferon response, can induce an IFNrelated DNA Damage Resistance Signature (IRDS) [53][54][55] and reduced tumor immunity 56 .…”

“…The enrichment of gene expression related to Type 1 IFN (IFN) signaling in high pORG tumors does not match the well-known transient effects of IFN (inhibition of infected/tumor cell proliferation 51 and upregulation of leukocyte effector functions 52 ). However, the downstream activity of IFN is pleiotropic and changes dramatically over time; in fact, chronic IFN signaling in cancer induces an IFN-related DNA Damage Resistance Signature (IRDS) of gene expression that is associated with tumor cell resistance to DNA damage [53][54][55] and escape from tumor immunity 56 . We used a set of IRDS genes reported to distinguish outcomes in cancer 53,55 and found a significant enrichment in high pORG versus low pORG tumors (Figure 4D, left panel).…”

JAK2 Alterations in Acute Lymphoblastic Leukemia: Molecular Insights for Superior Precision Medicine Strategies

“…While many JAK/STAT genes are expressed ubiquitously, mouse knockout and patient data suggest the JAK/STAT pathway is critically involved in stimulatory (rather than inhibitory) responses of immune effector cells in both innate and adaptive immunity, including mucosal cell integrity ( Ye et al, 2019 ). JAK3 is critical for γ c receptor signaling in T cells and natural killer cells, resulting in severe immunodeficiency if mutated, whereas JAK1 and TYK2 have more pleiotropic roles ( Ye et al, 2019 ; Musella et al, 2021 ). JAK2 activation occurs in response to a variety of cytokines and is essential for a plethora of normal cellular functions, particularly those involved in normal hematopoiesis ( Levine et al, 2007 ; Vainchenker and Constantinescu, 2013 ; Akada et al, 2014 ).…”