RNA sensing induced by chromosome missegregation augments anti-tumor immunity
Nobunari Sasaki1, Mizuki Homme1, Takahiko Murayama2
1Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
Abstract:
Viral mimicry driven by endogenous double-stranded RNA (dsRNA) stimulates innate and adaptive immune responses. However, the mechanisms that regulate dsRNA-forming transcripts during cancer therapy remain unclear. Here, we demonstrate that dsRNA is significantly accumulated in cancer cells following pharmacologic induction of micronuclei, stimulating mitochondrial antiviral signaling (MAVS)-mediated dsRNA sensing in conjunction with the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. Activation of cytosolic dsRNA sensing cooperates with double-stranded DNA (dsDNA) sensing to upregulate immune cell migration and antigen-presenting machinery. Tracing of dsRNA-sequences reveals that dsRNA-forming transcripts are predominantly generated from non-exonic regions, particularly in locations proximal to genes exhibiting high chromatin accessibility. Activation of this pathway by pulsed monopolar spindle 1 (MPS1) inhibitor treatment, which potently induces micronuclei formation, upregulates cytoplasmic dsRNA sensing and thus promotes anti-tumor immunity mediated by cytotoxic lymphocyte activation in vivo. Collectively, our findings uncover a mechanism in which dsRNA sensing cooperates with dsDNA sensing to boost immune responses, offering an approach to enhance the efficacy of cancer therapies targeting genomic instability.
Insights
Cancer therapy can induce double-stranded RNA (dsRNA) accumulation, activating immune responses. This dsRNA sensing, alongside DNA sensing, enhances anti-tumor immunity and may improve cancer treatment efficacy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Endogenous double-stranded RNA (dsRNA) mimics viral infection, activating innate and adaptive immunity.
- Mechanisms regulating dsRNA during cancer therapy are not fully understood.
Purpose of the Study:
- To investigate the role of dsRNA accumulation in cancer cells during therapy.
- To elucidate the pathways involved in dsRNA sensing and their impact on anti-tumor immunity.
Main Methods:
- Pharmacologic induction of micronuclei in cancer cells.
- Analysis of dsRNA sensing pathways, including MAVS, cGAS/STING.
- dsRNA sequencing to identify transcript origins.
- Treatment with monopolar spindle 1 (MPS1) inhibitor.
Main Results:
- Pharmacologic induction of micronuclei leads to significant dsRNA accumulation in cancer cells.
- Activated dsRNA sensing cooperates with dsDNA sensing to enhance immune cell migration and antigen presentation.
- dsRNA originates predominantly from non-exonic regions near accessible chromatin.
- MPS1 inhibitor treatment upregulates cytoplasmic dsRNA sensing, promoting anti-tumor immunity via cytotoxic lymphocyte activation.
Conclusions:
- dsRNA accumulation and sensing are key components of the anti-tumor immune response triggered by therapies inducing genomic instability.
- Cooperation between dsRNA and dsDNA sensing pathways boosts anti-tumor immunity.
- Targeting dsRNA sensing presents a novel strategy to enhance cancer therapy efficacy.
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