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

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.

Identification of differentially expressed HERV-K(HML-2) loci in colorectal cancer

“…The IFN-1 immune response mediated by dsRNA induction of multiple upregulated HERV transcripts has been identified as a critical anticancer mechanism of demethylation ( Chiappinelli et al, 2017 ). This stimulation that generated bidirectional HERV transcripts formed dsRNA detectable by cellular PRRs, and caused type I and type III IFN responses in colorectal cancer cells, reducing the antitumor activity of DNA methyltransferase inhibitors ( Vitiello et al, 2021 ). These dsRNAs can be assumed to be PAMPs for human PRR, stimulating innate immune responses through the TLR3 signaling pathway.…”

IL17RB and IL17REL Expression Are Associated with Improved Prognosis in HPV-Infected Head and Neck Squamous Cell Carcinomas

“…Previous studies have reported that viral infection may enhance anti-tumor immunity in cancer patients by activating type-I interferon signaling [89][90][91]. To estimate the effect of viral load on tumor immune infiltration, we compared tumor expression of immune cell transcriptional signatures (TS) [61,62] between 88 HPV-infected and 412 HPV-free tumors in 500 primary HNSCC tumor biopsies (Figure 1B).…”

Transcriptional and reverse transcriptional regulation of host genes by human endogenous retroviruses in cancers

“…Thus, HERVs are targeted as a promising internal strategy to enhance the anti-tumor immune responses by sensitizing tumor cells for immunotherapies. Vitiello et al (2021) reviewed the role of HERVs activation as a promising molecular predictive marker and immunotherapy target in cancers.…”