A group of scientists—coordinated by the Center for Neuroscience and Cell Biology of the University of Coimbra (CNC-UC), part of the Center for Innovative Biomedicine and Biotechnology (CiBB), and by Lund University—has succeeded in recreating for the first time in the laboratory, through cell reprogramming, Natural Killer (NK) cells, a type of immune system cell that acts on the front line of tumor defense.
This reprogramming was made possible by the creation of a platform called REPROcode, which will assist scientists in mapping and reprogramming immune cells. On this platform, researchers have created a library of more than 400 transcription factors—proteins capable of reprogramming most types of immune cells—identified by "barcodes", which allows them to track which ones promote the reprogramming of different types of immune cells.
"This tool allows us to test dozens of combinations of factors simultaneously, in order to identify which ones enable the production of various types of immune cells," explains CNC-UC researcher Carlos-Filipe Pereira, who coordinated the research.
CNC-UC researcher and study coordinator Carlos-Filipe Pereira and the study's first author, Ilia Kurochkin
In addition to enabling NK cell programming, the research also identified factors to improve the reprogramming of already known cell types, for which the combination was already known. This research thus paves the way for the development of new approaches to cellular immunotherapy.
Immunotherapy, which uses the patient's own immune system to fight cancer, is currently one of the most promising areas of medicine. However, a significant proportion of tumors and individuals do not respond to this type of treatment. Many types of immune cells are useful in immunotherapy, but they are rare in the blood and difficult to obtain directly from patients, making advances in their production in the laboratory, as was done in this study, very important.
The researchers also constructed a "roadmap" of the factors that control the formation of different immune cell lineages. Through cellular reprogramming, a cell can be converted into another distinct cell type, allowing immune system cells to be generated for immunotherapy purposes. However, most combinations of transcription factors remain unknown, and the map created in the study is an important contribution to advancing knowledge about these factors.
"Our approach works like a 'toolbox' that allows us to generate immune cells in the laboratory from cells that are easier to collect and replicate, such as skin cells. This strategy facilitates the development of more effective immunotherapies, reducing the risk of ineffectiveness in certain patients and enabling the advancement of new approaches against cancer and other immune system diseases," says Carlos-Filipe Pereira.
The leader of the CNC-UC research group on Immune Cell Reprogramming also states that "in the future, in addition to enabling the generation of cells that activate the immune system against cancer, this approach could be expanded to produce cells that teach it not to attack the body itself, paving the way for new therapies in autoimmune diseases such as diabetes or rheumatoid arthritis."
This study also involved researchers from institutions based in Sweden and Germany, such as the Lund Stem Cell Center and the Wallenberg Center for Molecular Medicine (at Lund University), the National Bioinformatics Infrastructure Sweden (with collaborations from Lund University and Stockholm University), the Institute of Computational Biology at Helmholtz Zentrum München, and Asgard Therapeutics.
The article A combinatorial transcription factor screening platform for immune cell reprogramming, published in the journal Cell Systems, is available at www.cell.com/cell-systems/fulltext/S2405-4712(25)00290-X.
Inês Amado da Silva with Catarina Ribeiro (UC)
