Liver Tumor Microproteins Could Be Key to Developing New Cancer Vaccines

In a new study published in Science Advances, scientists at Hospital del Mar Research Institute (IMIM) and their collaborators at the Center for Applied Medical Research (CIMA), the University of Navarra, and Pompeu Fabra University describe a group of proteins found exclusively in liver tumors that could help guide the development of novel cancer vaccines. Their work is detailed in a paper titled, “Microproteins encoded by noncanonical ORFs are a major source of tumor-specific antigens in a liver cancer patient meta-cohort.”

These so-called microproteins or noncoding ORF-derived (ncORF) peptides are small proteins expressed only by cancer cells that can be used to activate the immune system against cancer. Furthermore, these molecules are generated by genes that were once considered incapable of encoding proteins. The scientists discovered the proteins in this study by integrating and analyzing information from tumor and healthy tissue collected from over a hundred patients with hepatocellular carcinoma including RNA sequencing, immunopeptidomics, and ribosome profiling data. 

There is significant interest in cancer vaccines which rely on the immune system’s ability to recognize foreign proteins generated as a result of mutations in cancerous cells. The challenge lies with cancers with low mutation rates like liver cancers. Microproteins could be a solution in these cases. The results reported in the paper highlight the potential of using microproteins exclusively expressed in tumor cells as targets for new treatments. Specifically, the researchers identified “a subset of 33 tumor-specific long noncoding RNAs expressing novel cancer antigens shared by more than 10% of the HCC samples analyzed, which, when combined, cover a large proportion of the patients,” according to the paper.

In fact, “we have seen that some of these microproteins can stimulate the immune system, potentially generating a response against cancer cells,” said Puri Fortes, PhD, one of the paper’s authors and a researcher at CIMA as well as the Network Biomedical Research Center for Liver and Digestive Diseases (CIBERehd). According to the paper, when the team tested four ncORF-derived peptides in transgenic mice, they found that two of them could generate a significant immune response involving CD8+ T cells.  “This response can be enhanced with vaccines, similar to the coronavirus vaccines, but producing these microproteins. These vaccines could stop or reduce tumor growth,” said Fortes. 

Also, unlike other types of vaccines based on patient-specific mutations, a potential anticancer vaccine that targets ncORF peptides could be used to treat multiple people, as the same microprotein is expressed in various patients, the researchers noted.