Immunoncology: New findings in proteins tracing

Researchers identified thousands of specific peptides on the surface of cells for the first time. These so-called cryptic peptides mark tumor cells to a significant extent and may provide a new starting point for cancer immunotherapies.

Could cryptic peptides be a new therapeutic approach?

Using a newly developed method, researchers were able to identify thousands of specific peptides on the surface of cells for the first time. They showed that these so-called cryptic peptides mark tumor cells to a significant extent. These findings could provide a new starting point for cancer immunotherapies.

Almost all cells of the human body present fragments of cellular proteins on their surface, so-called human leukocyte antigens or HLA peptides, which play an important role in the immune response. If the immune system detects foreign HLA peptides, such as viral peptides on a virus-infected cell or mutated peptides on a tumor cell, T-cells eliminate the corresponding cell. The entirety of the HLA peptides presented on a cell is called the immunopeptidome of this cell.

New approach enables a comprehensive analysis for the first time

Besides the usual HLA peptides, there are also cryptic HLA peptides. These are derived from specific RNA sequences that do not contain information for a specific protein as is usually the case. In the past decades, only a few cryptic HLA peptides have been identified because they are very small and are quickly degraded in the cells. On the other hand, efficient computer programs for their analysis were lacking.

In a completely new approach, scientists in Germany have now combined several analytical methods that are particularly suitable for small peptides. "Using a novel bioinformatics method developed by us, we were able to identify for the first time thousands of cryptic HLA peptides in the immune peptides of a wide variety of tumors such as melanoma and breast cancer," explained Dr. Andreas Schlosser, research group leader at the Rudolf Virchow Center at the University of Würzburg.

The new bioinformatics approach is based exclusively on mass spectrometry data. As a result, it is now possible to systematically and comprehensively determine the cryptic HLA peptides. In addition, it was possible to clarify on which cells and to what extent cryptic peptides are present: "We were able to show that cryptic HLA peptides constitute a significant part of the immune peptides of tumors," explained Prof. Dr. Florian Erhard, head of a research group at the Institute of Virology at the University of Würzburg.

Effective targets for the immune system

It was already known from individual studies that cryptic peptides can trigger autoimmune reactions such as diabetes type 1 as well as immune responses against tumor cells. The new analyses provide evidence that certain cryptic HLA peptides are exclusively found on tumor cells. Such tumor-specific cryptic HLA peptides might thus prove to be worthwhile target structures for cancer immunotherapies. Scientists at the University of Würzburg and the Würzburg University Hospital are already investigating a selection of the identified peptides to determine whether they are suitable as targets for cancer immunotherapy.

Virus-infected cells also present cryptic HLA peptides that could be used as target structures in vaccinations. With their new method, the researchers thus have an effective tool in their hands to learn more about the general function and development of cryptic peptides. "We hope that our bioinformatics approach will provide us with a better understanding of autoimmune reactions as well as immune reactions against tumor cells and virus-infected cells," concluded Schlosser.

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