The DNA of waste has proven to be the source of "targets" for cancer immunotherapy – N + 1


Dendritic cells

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The non-coding part of the human genome, the so-called "junk" DNA, has proved to be an important source of peptide antigens that can be used for cancer immunotherapy, a group of scientists has discovered from Canada. They invented and published in the magazine Translational medicine science methodology that allows you to improve this process.

Our immune system is able to look for cancer cells and destroy them alone, but in some cases it does not notice them: from such "invisible" cells the tumors are obtained. But if you explain exactly what to look for – from something to smell, which is only inherent to cancer cells, she, like a hound dog, will be able to recognize and destroy them. This is the essence of antitumour immunotherapy. The "nose" and "teeth" of the immune system are its T lymphocytes, which control the cells for the presence of suspicious protein fragments. The cells have on their surface the so-called Major Histocompatibility Complex (MHC), to which the antigens, the peptides of this cell are attached. If a lymphocyte finds a cell with MHC with an antigen it is trained to recognize, it destroys it. Scientists have invented slipping dendritic cells – coaches, lymphocyte coaching – cancer-specific antigens, which they did not notice on their own, thus activating the immune response to them. Due to the complexity of the research at the moment, many effective antigens suitable for vaccine production have not been found.

A group of scientists led by Celine Laumont of the University of Montreal has found a new way to find the peptides suitable for the training of the immune system. Nowadays, the so-called inverse immunology is often used for this, when, on the basis of esophical sequencing, the regions of the characteristic mutant gene are found in the tumor cells, and are then filtered, whose products can bind well to the # 39; MHC. At the same time, most of the antigens found are "dummies" because the method does not take into account the remaining stages of the interaction of MHC with the antigen in addition to the binding, so it is necessary to further verify the candidates with additional methods . As a result, the number of potential targets for immune system activation is small.

In this case, only the mutant antigens are usually considered, while the unchanged sequences, which are expressed only in tumor cells, remain outside the scope of analysis. Also excluded from the research non-coding parts of the genome, such as intergenic regions or introns. The latter occupy a large part of the genome, may contain many cancer mutations and, in principle, participate in transcription and therefore protein synthesis. Having eliminated these two shortcomings of the existing methodology, the researchers found new promising antigens.

For this purpose, the entire RNA of two tumor cell lines was sequenced and analyzed in two ways. The first was aimed at finding active genes with specific substitutions for single nucleotide cancer in the coding sequence. The second aimed to detect any areas of RNA that were abundant in tumor cells and absent in normal cells. The search for suitable candidates in the combined database of these fragments and the subsequent validation of the results produced 14 potential antigens for one line of cancer cells and for the other 7. It was discovered that most of them were due to the translation of coding of the genome and would be skipped using the standard protocol.

Subsequently, the researchers tested the efficacy of the five most promising peptides in mice. They immunized them with dendritic cells with these antigens and then injected tumor cells. The same manipulations were performed with control mice, but the dendritic cells were free of corresponding antigens. Three candidates proved to be particularly effective: they greatly prolonged the lives of mice and the level of T cells trained in the search for these antigens was superior to control. Then they passed from the experiments on the seven-line mice of primary human cancer and, in a similar way, they found 22 potential antigens, two of them mutants, and the rest was erroneously expressed.

The new method has allowed us to significantly expand our understanding of potential cancer antigens: it has emerged that a large number of these can be detected by examining non-coding regions of the genome, ignored by the standard research strategy. If these antigens are found abundantly in the tumor cells and are suitable for the "formation" of the lymphocytes, they can be used for vaccination. You can read more about this and other immunotherapy approaches in our review material.

Vera Mukhina


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