Suppression of the mRNA export pathway dampens viral mimicry response and promotes tumor immune evasion [RNA-seq]

Transcriptional induction of retroelement transcripts through therapeutic interventions elevates cytosolic double-stranded RNA (dsRNA) levels to trigger viral mimicry response and anti-tumor immunity. Therapeutic interventions that transcriptionally induce retroelement transcripts lead to elevated levels of cytosolic double-stranded RNA (dsRNA), thereby triggering a viral mimicry response and enhancing anti-tumor immunity. Despite the promising implications, clinical studies have revealed substantial variations in the therapeutic induction of viral mimicry response in different cancer patients, with the underlying mechanisms remaining largely elusive. In this study, we illuminate the pivotal role of the mRNA export pathway in viral mimicry response and anti-tumor T cell immunity. Notably, epigenetic and posttranscriptional induction of cytosolic dsRNAs necessitates the mRNA export pathway to transport the nuclear-transcribed retroelement transcripts into the cytoplasm, which is posttranscriptionally suppressed by the RNA exosome in coactivator-associated arginine methyltransferase 1 (CARM1)-expressing tumor cells. Mechanistically, Carm1 restricts the nuclear export of retroelement transcripts through transcriptional elevation and posttranslational stabilization of the RNA exosome, which hydrolyzes the critical nuclear RNA export adaptor transcripts Ddx39a and Alyref. Collectively, our study underscores the vital importance of the mRNA export pathway in viral mimicry response and suggests that enhancing its activity through Carm1 or RNA exosome inhibition could reinforce therapy-induced viral mimicry response, thus holding the potential to overcome tumor immune escape and immunotherapy resistance. We conducted total RNA sequencing (RNA-seq) on parental and Carm1 knockout (Carm1-/-) B16-F10 cells derived from mouse tumor tissues. Total RNA-seq was also performed on control B16-F10 cells and those with DDX39A overexpression. mRNA sequencing (mRNA-seq) was performed on whole cells, as well as cytoplasmic and nuclear fractions, from control, Carm1-/-, Ddx39a-/- Carm1-/-, and Alyref-/- Carm1-/- B16-F10 cell lines. We carried out mRNA-seq on whole cells, cytoplasm, and nucleus of control, Ddx39a-/- and Alyref-/- B16-F10 cells treated with Decitabine. mRNA-seq was executed on whole cells, along with their cytoplasmic and nuclear components, from parental, Ddx39a-/- and Alyref-/- MC38 cells. We conducted total RNA-seq on control, Dis3-/- and Exosc1-/- B16-F10 cells.