Induction of immunogenic cell death in cancer cells using modified ssRNAs
Cancer immunotherapy is showing great promise against numerous cancer types in clinical trials. Consequently, this market is projected to rapidly grow to over $200 billion by 2021. Among the list of effective immunotherapies are agents that target pathogen recognition receptors (PRR). These therapies not only stimulate and activate the immune system, but they have also been shown to elicit direct killing of tumor cells. RNA is one of the most prominent PRR ligands and, as such, derivatives of RNA are frequently used in clinical immunotherapy studies (e.g. PolyI:C). However, a major limitation of RNA-based agents is their susceptibility to nuclease degradation, making them extremely labile molecules. A stable RNA derivative that can persistently stimulate PRRs would have clear application for immunotherapy.
Dr. Bruce Sullenger and colleagues have developed a novel stabilized ssRNA molecule possessing a 5’ tri-phosphate and 2’-fluoro-modified pyrimidine (5’-3p 2’F ssRNA) that mimics dsRNA and can, thus, stimulate dsRNA-cognate PRRs. Internalization of 5’-3p 2’F ssRNA by tumor cells leads to pronounced cytotoxicity across a broad range of cancer types. Additionally, treatment of cancer cells with 5’-3p 2’F ssRNA promotes to the surface expression of the danger-associated membrane protein, calreticulin, which functions as an “eat me” signal for professional phagocytic cells. Finally, addition of 5’-3p 2’F ssRNA to tumor cells induces the production of type I interferons, which elicit potent immune stimulatory and tumoricidal activity. The diverse antitumor effects this agent has on cancer cells, as well as its enhanced stability, makes it an appealing option as an adjuvant or stand-alone immunotherapy.
5’-3p 2’F ssRNAs have increased nuclease resistance compared to RNA and similar analogues. Furthermore, this immunotherapy acts on innate immune sensors and is, therefore, less likely to be affected by tumor heterogeneity.