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Review
. 2021 Dec 2:12:782852.
doi: 10.3389/fimmu.2021.782852. eCollection 2021.

Antiviral Responses in Cancer: Boosting Antitumor Immunity Through Activation of Interferon Pathway in the Tumor Microenvironment

Glauco Akelinghton Freire Vitiello  1 , Wallax Augusto Silva Ferreira  1   2 , Vladmir Cláudio Cordeiro de Lima  3 , Tiago da Silva Medina  1   4
Affiliations
Review

Antiviral Responses in Cancer: Boosting Antitumor Immunity Through Activation of Interferon Pathway in the Tumor Microenvironment

Glauco Akelinghton Freire Vitiello et al. Front Immunol. .

Abstract

In recent years, it became apparent that cancers either associated with viral infections or aberrantly expressing endogenous retroviral elements (EREs) are more immunogenic, exhibiting an intense intra-tumor immune cell infiltration characterized by a robust cytolytic apparatus. On the other hand, epigenetic regulation of EREs is crucial to maintain steady-state conditions and cell homeostasis. In line with this, epigenetic disruptions within steady-state cells can lead to cancer development and trigger the release of EREs into the cytoplasmic compartment. As such, detection of viral molecules by intracellular innate immune sensors leads to the production of type I and type III interferons that act to induce an antiviral state, thus restraining viral replication. This knowledge has recently gained momentum due to the possibility of triggering intratumoral activation of interferon responses, which could be used as an adjuvant to elicit strong anti-tumor immune responses that ultimately lead to a cascade of cytokine production. Accordingly, several therapeutic approaches are currently being tested using this rationale to improve responses to cancer immunotherapies. In this review, we discuss the immune mechanisms operating in viral infections, show evidence that exogenous viruses and endogenous retroviruses in cancer may enhance tumor immunogenicity, dissect the epigenetic control of EREs, and point to interferon pathway activation in the tumor milieu as a promising molecular predictive marker and immunotherapy target. Finally, we briefly discuss current strategies to modulate these responses within tumor tissues, including the clinical use of innate immune receptor agonists and DNA demethylating agents.

Keywords: antitumor immunity; antiviral immune response; endogenous retroviral elements; epigenetic regulation; immunotherapy; interferons; oncolytic viruses.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Activation of IFN-I/III response by viral sensing through PRRs. Sensing of viral molecules by plasma membrane (TRL4), endosomal (TLR3, 7, 8 and 9) or cytosolic (RLRs and cGAS) PRRs activate signaling pathways culminating in the expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-18 and TNFα) by NF-κB, AP-1 and IRF5 transcription factors and of IFN-I and IFN-III by IRF3 and IRF7 (left). IFNs act though transmembrane receptors to activate STAT1, STAT2 and IRF9. This complex then translocates to the nucleus to govern the expression of several interferon-stimulated genes (right), which mediate an antiviral state leading to cell apoptosis, cytostasis, antigen presentation and expression of viral restricting factors. Created with BioRender.com.
Figure 2
Figure 2
Activation of IFN-I/III responses in TME lead to enhanced anti-tumor response and tumor control. Poorly immunogenic (“cold”) tumors might be converted to highly infiltrated tumors (“hot”) through the activation of IFN-I/III responses. This might be accomplished through several strategies, such as genotoxic therapies and triggering of innate immunity receptors involved in antiviral responses. IFN-I/III mediate this phenomenon by its actions on tumor cells, inducing immunogenic cell death and enhanced antigen presentation as well as by its effects in activating anti-tumor immune cell populations, such as dendritic cells, T lymphocytes and natural killer (NK) cells. Created with BioRender.com.
Figure 3
Figure 3
DNA-damaging agents trigger IFN-I/III responses through activation of cGAS/STING and TLR3 pathways. DNA-damaging agents cause DNA leakage into cytoplasm as well as induce dsRNA formation, leading to the activation of cGAS and TLR3. Also, blebs from dying cell containing DNA and dsRNA are captured by dendritic cells and also sensitizes cGAS and TLR3 in these cells. These pathways culminate in IFN-I/III production by both cells, leading to efficient dendritic cell activation and T cell priming, thus enhancing anti-tumor responses. This process mediates the response to genotoxic therapies and found the base for their use as adjuvants for ICB therapies. Created with BioRender.com.
Figure 4
Figure 4
Epigenetic modulators unleash EREs expression culminating in IFN-I/III secretion through activation of MDA5. Treatment with DNA hypomethylating agents (DHA) and histone deacetylase inhibitors (HDACi) lead to chromatin modifications and unleashing of endogenous retroviral elements (EREs) in tumor cells. The intermediates formed by these elements during their replication sensitize RIG-like receptors in the cytosol, such as MDA-5 and RIG-I, which activate IRF7/9 and the production of IFN-I/III. ERE-derived RNAs might also be translated in tumor cells generating tumor-associated antigens that may be recognized by CD8+ T cells. In this manner, DHA and HDACi increase tumor immunogenicity and might be explored as adjuvants for ICB therapies. Created with BioRender.com.
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