The Pereira research group has previously shown that it is possible to reprogram human skin cells into dendritic cells that strengthen the immune system. However, the efficiency of these reprogrammed cells has been shown to be very low. New studies now indicate that there are ways to increase the efficiency of these reprogrammed cells by over 75%. These findings provide mechanistic insights into human Type 1 conventional dendritic cells (cDC1) specification and reprogramming, and represent a platform for potential use in cancer immunotherapy. The results were published earlier this month in Science Immunology.
Our dendritic cells (DC) are the guard posts of the immune system and they patrol our bodies for bacteria, viruses or cancer cells. When DC finds a foreign particle, they break it down into smaller pieces - antigen - and present the pieces on the cell surface to the immune system's killer cells. In this way, the killer cells learn which infectious agents and cancer cells to seek out and kill. In several studies, researchers have investigated various cell therapies that use DC to strengthen the patient's own immune system to fight cancer. But cancer can affect the dendritic cells so that they are lost or become dysfunctional. Therefore, new ways are needed to reprogram other cells to become immune cells, with the same capacity as "natural" dendritic cells.
Filipe Pereira, research group leader at Lund Stem Cell Center, has previously identified a combination of three transcription factors (specialized protein) that have made it possible for human skin cells (fibroblasts) to be reprogrammed into dendritic cells. The study was the first of its kind and showed how to use cell programming to generate immune cells to fight cancer. But - unlike cells in mice - it has been shown that the efficiency of human cells is less than one percent.
It is not clear why human cells are more difficult to reprogram, but it seems to be a general problem that has been a major obstacle to being able to transfer our results to the clinic. To fully understand the process of reprogramming, we therefore used single-cell analysis - a method for mapping the composition of tissues and molecularly characterizing cell types and their signaling pathways.
The image below illustrates how the three transcription factors (the snowflake triad) reprogram cells into dendritic cells:
With the single-cell analysis, the researchers were able to follow the transformation of the skin cells into dendritic cells, how the three transcription factors cooperate and how the genetic information was transferred and "silenced" the cell's original identity. By identifying the genes that were expressed, they understood what limited the reprogramming process in human cells.
Because the dendritic cells are supposed to trigger the immune system, they need to have inflammatory properties. Increasing the inflammatory properties of the cells proved to be an important piece of the puzzle for higher efficiency. By understanding the process behind the reprogramming, we managed to increase the efficiency to over 75 percent - a very high figure in these contexts.
In their experiments, the researchers reprogrammed three different types of human cells: skin cells from the fetus, skin cells from adults and stem cells from bone marrow. With the new way of reprogramming them, the efficiency of all types of cells has increased drastically.
This is very positive and opens up the possibility of inducing cancer immunity with the help of cell reprogramming. The next step is to carry out the improved reprogramming experiments in animal models.
The study referred to in this article was funded by the European Research Council (ERC) Cancer Foundation, the Swedish Research Council, the NovoNordisk Foundation, The Knut and Alice Wallenberg Foundation, the Faculty of Medicine at Lund University and Region Skåne.
