Alternative Splicing in Cancer and Immune Cells

Abstract

Splicing is a phenomenon enabling the excision of introns from pre-mRNA to give rise to mature mRNA. All the 20,000 genes of the human genome are concerned by this mechanism. Nevertheless, it is estimated that the proteome is composed of more than 100,000 proteins. How to go from 20,000 genes to more than 100,000 proteins? Alternative splicing (AS) is in charge of this diversity of proteins. AS which is found in most of the cells of an organism, participates in normal cells and in particular in immune cells, in the regulation of cellular behavior. In cancer, AS is highly dysregulated and involved in almost all of the hallmarks that characterize tumor cells. In view of the close link that exists between tumors and the immune system, we present in this review the literature relating to alternative splicing and immunotherapy. We also provide a global but not exhaustive view of AS in the immune system and tumor cells linked to the events that can lead to AS dysregulation in tumors.

Covalent Targeting of Splicing in T Cells

“…6A). This intriguing observation, together with the recent identification of small molecules targeting additional splicing factors/regulators, such as the spinal muscular atrophy drug risdiplam[43], covalent modulators of the RNA-binding protein NONO[7], and small-molecule protein degraders of RBM39[44], motivated us to perform a more in-depth study of splicing factors and splicing regulators that can be targeted with small-molecule electrophiles in the context of therapeutic discovery for cancer treatment and immune modulation[17, 22, 45–48]. To address this question, we first compiled an exhaustive list of proteins involved in splicing (Fig.…”

Roles and mechanisms of aberrant alternative splicing in melanoma — implications for targeted therapy and immunotherapy resistance

“…Second, analyzing whether alternative splicing events within a tumor occur elsewhere in the body and not only in the healthy tissue surrounding the tumor is essential [ 21 ]. Furthermore, identifying alternative splicing events at the subclonal level in tumors is challenging [ 147 ]. These findings indicate the great potential of splice variants in melanoma-targeted therapy and immunotherapy.…”

Classification of clinically actionable genetic mutations in cancer patients

“…Through this, we can penalize the words that occur most frequently in a lot of documents and assign high weightage to terms that are important to specific documents as they can be the defining features or good predictors of a class. This is accomplished by taking the product of two metrics, that is, the number of times a word appears in a document, called term frequency, and the inverse document frequency of the word, which is a measure of whether a term is common or rare across the corpus of documents Bernard (2022) . It uses a measure of how often the words appear in the documents, and the word count is weighted by that measure Kumar (2020) .…”