Chimeric RNAs as Novel Neoantigens for Extracellular Vesicles-Based Vaccines Against Cancer

Cancer vaccines work by training the immune system to recognize molecules that are found only in cancer cells. Most experimental cancer vaccines focus on neoantigens, proteins that are created by DNA mutations in tumors. However, many cancers have very few mutations, making it difficult to identify suitable vaccine targets.

Researchers from Jinan University explored an alternative source of cancer specific neoantigens by focusing on chimeric RNAs. These unusual RNA molecules are produced when abnormal RNA splicing joins pieces of different RNA sequences together, creating unique chimeric proteins that are found in tumor cells but not in healthy tissues.

The researchers demonstrated that one of these tumor specific chimeric RNAs, known as ASTN2-PAPPA antisense chimeric RNA, or A-PaschiRNA, can trigger an immune response. Because the resulting chimeric protein is unique to cancer cells, it has the potential to serve as a neoantigen that helps the immune system distinguish tumors from healthy tissue.

To deliver this new type of cancer vaccine, the team developed an extracellular vesicle based approach. Extracellular vesicles are naturally released by cells and can transport proteins and RNA between cells. In this work, the researchers loaded extracellular vesicles with chimeric RNAs and tested the vaccine in mouse models of esophageal squamous cell carcinoma.

The experimental vaccine slowed tumor growth in the animal models, demonstrating that chimeric RNAs can serve as effective targets for cancer immunotherapy. This strategy could be particularly valuable for cancers with a low mutation burden, where traditional mutation based neoantigens are scarce or absent.

Another advantage of extracellular vesicle based vaccines is that they are cell free. Compared with vaccines that require living immune cells, extracellular vesicles may be easier to manufacture, store, modify, and deliver while still stimulating a strong immune response.

Although additional research is needed before this approach reaches the clinic, the findings suggest that chimeric RNAs could significantly broaden the range of targets available for therapeutic cancer vaccines. Combining these novel neoantigens with extracellular vesicle delivery may open new opportunities for treating cancers that have previously been difficult to target with immunotherapy.