Cancer under pressure
The immune system has limited the heterogeneity of cancer cells
Vera Mukhina, N+1
Scientists looked at how the immune system interacts with genetically heterogeneous cancer cells. According to a paper published in Science Immunology, the immune system limits the potential diversity of tumor cells by destroying the most immunogenic.
The cells inside each tumor are quite heterogeneous. The reason for this is their genomic instability, when different cells of the population quickly accumulate different mutations. This diversity creates the ground for the selection of the most adapted cancer clones, in particular, those able to escape the attention of the immune system. The latter plays a very important role in protecting the body from malignant neoplasms and cleanses most cancer cells in the early stages. Therefore, under the pressure of the immune system, those cancer clones that have passed the "invisibility" test survive. Despite the general acceptance of this idea, there is quite little information about what is happening at the level of the cell population and how exactly the immune system reduces the heterogeneity of the cancer cell population.
A group of French scientists decided to use color barcoding to clarify this issue. This technology makes it possible for cells to produce different fluorescent proteins or combinations of them and, accordingly, look different under the microscope. At the same time, color differentiation is preserved from generation to generation, so that all descendants of the same cell (clones) will be equally colored. The scientists took the lymphoma cells of mice, colored them using barcoding in five colors and injected them into other mice, while each individual received the same number of cells of each color, from which a neoplasm can later develop. Scientists have suggested that in the absence of selection, the color ratio will change little, while a decrease in cell heterogeneity and the appearance of dominant clones will affect the color distribution.
The descendants of the injected cancer cells populated mainly – as befits lymphoma – bone marrow, spleen and lymph nodes, but occasionally were found in other tissues unrelated to the lymphatic system. It turned out that the populations of cancer cells in non-lymphoid tissues were almost always monochrome, that is, they were probably descendants of a single cell.
Successive micrographs of the bone marrow show how its gradual colonization by multicolored cancer cells occurs (Milo et al./Science Immunology).
Often whole chromosomes are lost in cells, and their absence affects the composition of possible antigens and the corresponding immune response. Scientists have confirmed this idea using the example of a Y chromosome carrying a male-specific H-Y antigen. The mice from which the lymphoma cells were obtained were males and therefore had a Y chromosome. However, due to genetic instability, about 28% of the tumor cells have lost it, and with it the H-Y antigen. When ingested into a female, H-Y was supposed to act as a cancer antigen and cause an immune response in part of the cells, thereby simulating a situation in which only a part of the cancer cells is visible to the immune system. Indeed, the stripping of cells with and without the Y chromosome by the immune system went differently and depended on the sex of the mouse. In females, cell growth was slower and dominant clones were clearly expressed. A detailed investigation revealed that all of them are missing the Y chromosome. In males, such a sharp decrease in clonal diversity was not observed and the frequency of absence of the Y chromosome was approximately at the same level as in donor mice.
One of the most promising methods of cancer treatment is immunotherapy, in particular the so-called checkpoint inhibition. The researchers tried to cure mice using this method and found that it significantly reduces clonal diversity even when treatment does not help to reduce the overall growth of the tumor. The authors of the article believe that this effect can be used in conjunction with other types of therapy for which the genetic heterogeneity of the cancer population is an obstacle.
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