Cancer Immunotherapy: Identifying Suitable Antigens Using Mass Spec
New cancer therapies fight tumors using the immune system. A basic principle of these therapies is to find out which molecules the immune system recognizes on cancer cells. A team from the Technische Universität München (TUM) and the Max Planck Institute for Biochemistry has now directly identified suitable protein structures on tumor samples from patients. This opens up new possibilities for individually coordinated cancer treatments.
In the course of evolution, the immune system has developed sophisticated mechanisms to fight viral and tumor diseases. An important actor are the so-called T cells. They can recognize peptides, small protein structures, on body-specific cells. The peptides are "presented" by the cells on the surface. They thus indicate which molecules are located in their interior. The peptides presented can, for example, indicate that a cell is infected by a virus or that its genotype has mutated - a feature of tumor cells.
Peptides identified by immune cells are called antigens. T cells that recognize antigens can initiate a reaction in which the affected cells are destroyed. In recent years, research teams, including at the TUM, have successfully used this property for cancer treatment. There are different approaches for this. Vaccination with an antigen can stimulate the body to produce enhanced T cells. Another possibility is to enrich T cells that are "trained" to specific antigens and transfer them into the body.
In both cases it is important to know which antigens the T cells can identify viruses or tumors. The number of peptides that can be found on carcinogenic cells and cancer cells is high. The number of potential candidates in the search for suitable antigens is correspondingly high. The authors of the current study identified approximately 100,000 different peptides in tumor tissue samples from 25 skin cancer patients alone. The T-cell peptides are particularly well recognizable on tumors that have mutations, that is, their structure is altered. Which peptides are mutated and how they are altered is usually different from a person who is sick to a diseased person.
TIME-CONSUMING AND ERROR-PRONE SEARCH
So far, the search for the mutated peptides, which are actually presented on tumor cells, was a complex and error-prone process. First, the genome had to be broken down from tumor cells, a process that took itself in itself for one to two weeks. On the basis of the obtained data, prediction programs can be used to calculate which peptides could occur with corresponding changes on the cell surface. Whether these molecules really exist and are presented on the surface had to be found only in lengthy laboratory experiments.
A team led by Angela M. Krackhardt , Professor of Translational Immunotherapy in the III. Medical Clinic of the Klinikum rechts der Isar, TUM and Professor Matthias Mann from the Department of Proteomics and Signal Transduction at the Max Planck Institute for Biochemistry has developed an alternative to this process. In the specialist magazine "Nature Communications", Krackhardt and Mann portray their approach. Unlike previous methods, it is not based on prediction models but on the identification of the peptides presented on the tumor surface using a mass spectrometer.
MEETING AND SAVING TIME
The gene sequence, ie the blueprint of the tumor cells, is also broken down for the new method. In parallel, the peptides are detached from the surface of the tumor tissue and examined by mass spectrometry. In simple terms, the device will identify the molecules present on the tissue surface of the tumors. If both information are combined, the actual antigens that contain mutations can be found with a high hit rate.
The team around Krackhardt and Mann was able to demonstrate the clinical relevance of the new method: in the blood of skin cancer patients, they found T cells that used antigens for the detection of tumor cells that could previously be identified using mass spectrometry.
The new approach offers numerous advantages. By eliminating simulations and laboratory tests, he provides information on mutated peptides in the tumor cells in much shorter time. "For the first time, we investigated not only cultured, genetically identical cells in the mass spectrometer, but inhomogeneous tumor tissue from real patients," Matthiasmann adds. "This allows us a much more differentiated view of the molecular properties of the tumor." In addition, the method is particularly sensitive. As a result, promising research approaches, such as the role of phosphorylated peptides, have already emerged from the data of the current study.
According to Angela Krackhardt, there is little to hinder a clinical application of the method. "Our approach opens up new possibilities for personalized treatment of cancer," Krackhardt adds. "By accelerating the identification of suitable antigens, we would be able to provide individual vaccines or T-cell therapies for our patients within a reasonable time period of weeks to a few months."
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