Scientists reverse immunotherapy-resistance by suppressing EPIC1 in mouse model of breast, prostate, and pancreatic cancer

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"... when tumor cells find ways to evade immune detection—like suppressing immune signaling pathways. One such mechanism is the use of long noncoding RNAs (lncRNAs), which have been found to regulate cancer biology and immune evasion. These lncRNAs render immunotherapies, like the PD-1 inhibitor, pembrolizumab, ineffective. ...

In a new study ... scientists focus on the lncRNA, EPIC1, and its interaction with histone methyltransferase, EZH2, a known contributor of tumor immune evasion in cancer cells. ...

The researchers found that EPIC1 suppresses the accumulation of cytoplasmic dsRNA and type I interferon (IFN) responses in multiple cancer cell lines, including breast cancer, prostate cancer, and pancreatic cancer. EPIC1 and EZH2 were also shown to work together to repress the expression of immunogenic REs, suggesting a shared pathway for immune evasion.

The study authors write, "Collectively, these results suggest that EPIC1 suppression promotes an antiviral-like type I IFN response with potential antitumor effects." ..."

From the editor's summary and abstract:

"Editor’s summary

Cytoplasmic double-stranded RNAs (dsRNAs), such as those derived from endogenous retroviruses, stimulate type I interferon production to promote antitumor responses. Pattarayan et al. found that the long noncoding RNA EPIC1, which interacts with the epigenetic regulator EZH2, limited antitumor immunity by repressing the expression of EZH2-regulated retroelements.

Loss of EPIC1 in cancer cell lines increased cytoplasmic dsRNA amounts, stimulated interferon-β production, and promoted immune cell activation.

In humanized mice bearing breast cancer xenografts, EPIC1 knockdown reduced tumor growth and enhanced immunotherapy efficacy, suggesting its potential as a therapeutic target.  ...

Abstract

Increases in retroelement-derived double-stranded RNAs (dsRNAs) in various types of cancer cells facilitate the activation of antitumor immune responses. The long noncoding RNA EPIC1 interacts with the histone methyltransferase EZH2 and contributes to tumor immune evasion. Here, we found that EPIC1 in tumor cells suppressed cytoplasmic dsRNA accumulation, type I interferon (IFN) responses, and antitumor immunity.

In various cancer cell lines, knockdown of EPIC1 stimulated the production of dsRNA from retroelements and an antiviral-like type I IFN response that activated immune cells. EPIC1 inhibited the expression of LINE, SINE, and LTR retroelements that were also repressed by EZH2, suggesting a potential role for the EPIC1-EZH2 interaction in regulating dsRNA production.

In a humanized mouse model, in vivo delivery of EPIC1-targeting oligonucleotides enhanced dsRNA accumulation in breast cancer xenografts, reduced tumor growth, and increased the infiltration of T cells and inflammatory macrophages into tumors.

Furthermore, EPIC1 knockdown improved the therapeutic efficacy of the immunotherapy drug pembrolizumab, a PD-1 inhibitor, in the humanized mouse model. Together, our findings establish EPIC1 as a key regulator of dsRNA-mediated type I IFN responses and highlight its potential as a therapeutic target to improve the efficacy of immunotherapy."

Scientists reverse immunotherapy-resistance by suppressing EPIC1 in mouse model of breast cancer

The lncRNA EPIC1 suppresses dsRNA-induced type I IFN signaling and is a therapeutic target to enhance TNBC response to PD-1 inhibition (no public access)