Sayak Banerjee, Amity University Kolkata
According to the scientists at Baylor College of Medicine, antiviral immune pathways in triple-negative breast cancers (TNBC) can be activated by therapeutics targeting RNA splicing along with the stimulation of tumour cell death. Around 10-20% of breast cancers are triple-negative, which signifies that they are negative not only for estrogen and progesterone receptors but also surfeit HER2 protein. Hence, TNBC does not respond to many common therapies for breast cancer.
RNA splicing, the removal of non-coding introns, is usually uncontrolled in tumours, resulting in tumour growth but also making the tumour hypersensitive to spliceosome-targeted therapies (STTs). TNBC are one of many invasive cancers that are receptive to Spliceosome-targeted therapies and these therapeutics are modulators of anti-tumour immunity. It was found that the interference of STTs with RNA splicing in TNBC creates an accumulation of endogenous mis-spliced intron RNA in the tumour cell cytosol. Most of these anomalous RNA form double-stranded structures, which after being identified by the antiviral immune pathways eventually trigger apoptosis and transmit signals to the body’s immune system that generate an inflammatory response.
The study suggested that yet without using Spliceosome-targeted therapies the immune system could be stimulated by a tumour cell’s endogenous mis-spliced RNA. A correlation between mis-spliced RNA and immune signatures is seen in the data, even in the immune-cold tumours which do not have high levels of T cells. High levels of mis-splicing lead to cellular stress in breast cancer and this RNA splicing stress might be present in many types of cancers and disease states. The researchers hypothecated about the endogenous mis-spliced RNA being used as a clinical biomarker to find the cancers sensitive to immunotherapy. They said that further analysis is needed to ascertain if more patients could be made eligible for immunotherapy by STTs activation of anti-tumour immune pathways.
Immunotherapies are very efficacious yet they only work in a minority of cancer patients. Thus, a new mechanism is discovered by which an interface is made between cancer and the immune system giving rise to different approaches to utilize for the benefit of patients.
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Source: Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer https://doi.org/10.1016/j.cell.2020.12.031
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