Filipe Pereira, professor of molecular medicine at Lund University
Photo Credit: Courtesy of Lund University
Scientific Frontline: "At a Glance" Summary
- Main Discovery: Researchers at Lund University established a high-throughput screening platform and a library of over 400 immune-related transcription factors to decode the specific "recipes" required to reprogram accessible somatic cells into distinct immune cell identities.
- Methodology: The study utilized unique DNA barcodes attached to each transcription factor, allowing the simultaneous tracking of thousands of combinatorial possibilities to determine which specific factor groups drive conversion to desired immune lineages.
- Key Data: This four-year project successfully identified reprogramming protocols for six different immune cell types, including Natural Killer (NK) cells, which were previously impossible to generate through direct reprogramming.
- Context: Prior to this breakthrough, the specific reprogramming factors had been mapped for only four of the human body's more than 70 distinct immune cell types, limiting the development of synthetic immunotherapies.
- Significance: The platform enables the production of rare, patient-specific immune cells from abundant sources like skin fibroblasts, potentially expanding immunotherapy applications from cancer treatment to autoimmune diseases and regenerative medicine.
To reprogram readily available cells into specific immune cells that fight various diseases, one must know the “recipe” for the transformation. Researchers at Lund University have now created a library of the 400 factors needed for reprogramming and have begun the work of finding the right combination – the recipe – for each type of immune cell.
Our immune system consists of different types of cells that specialize in different functions to protect us from disease. Normally, the immune system is very good at finding and destroying viruses, bacteria, and cancer cells. But at the same time, these intruders can also develop strategies to evade the immune system's attacks.
Immunotherapy and new cancer treatments
"Immunotherapy is a group of treatments that help the body defend itself by strengthening or controlling the immune system. In cancer, current approaches include, for example, CAR-T cell therapy, where a patient's own T cells are genetically modified to better find and kill cancer cells. It is one of the most promising methods in modern medicine," says Ilia Kurochkin, postdoc at Lund University and first author of the study.
Challenges and the need for cell reprogramming
Despite advances, not all patients respond to current treatments. In addition, despite their importance for immunotherapy, many of our immune cells are rare and difficult to extract from the patient's blood. Being able to reprogram easily accessible cells into rare immune cells is therefore promising for future immunotherapies, giving hope for the unresponsive patients of the current forms of immunotherapy.
"However, progress has been limited because we still do not fully understand the factors that control the identity and function of cells. To convert a more accessible cell – for example, a skin cell – into a specific immune cell, we first need to know which factors are needed for reprogramming and generating that particular identity," says Ilia Kurochkin.
A new platform for discovering immune cell “recipes”
The researchers therefore wanted to develop a technique to identify the factors needed to reprogram rare immune cell populations. They created a library of over 400 immune-related factors, each labelled with a unique DNA barcode. Using this system, they were then able to test thousands of combinations simultaneously and track, which triggered the conversion to specific immune cells.
"It took us four years to develop the screening technique and complete the library. This is the foundation for subsequently creating “recipes” for reprogramming immune cells. Depending on the type of cell you want to reprogram that can be harnessed to treat multiple diseases, you go to the “recipe book” to see the instructions for reprogramming," says Filipe Pereira, Professor of Molecular Medicine at Lund University, who led the study.
Future applications beyond cancer
The researchers have developed a platform to systematically discover such “recipes” and have already identified recipes for six different types of immune cells. The goal is to continue finding recipes for reprogramming more types of immune cells and their functional states. The method also made it possible for the first time to produce immune cells that were previously not accessible through reprogramming, such as natural killer cells (NK cells), which are crucial for fighting cancer cells. In the future, the team aims to extend this technology beyond cancer to other diseases involving the immune system.
"The goal is to create “recipes” for reprogramming all our immune cells, which can accelerate the development of new therapeutic strategies against cancer, autoimmune diseases and tissue repair that are tailored to each individual's immune system. The next step is to prove the principle of harnessing the immune cell reprogramming beyond cancer and test new combinations in autoimmune disease models," concludes Filipe Pereira.
Funding: Novo Nordisk, Knut and Alice Wallenberg Foundation, Swedish Research Council, Cancerfonden, European Research Council, European Innovation Council
Published in journal: Cell Systems
Title: A combinatorial transcription factor screening platform for immune cell reprogramming
Authors: Ilia Kurochkin, Abigail R. Altman, Inês Caiado, Diogo Pértiga-Cabral, Evelyn Halitzki, Mariia Minaeva, Olga Zimmermannová, Luís Henriques-Oliveira, Dominik Klein, Malavika Nair, Daniel Oliveira, Laura Rabanal Cajal, Ramin Knittel, Cora Feick, Markus Ringnér, Marcel Martin, Branko Cirovic, Cristiana F. Pires, Fabio F. Rosa, Ewa Sitnicka, Fabian J. Theis, and Carlos-Filipe Pereira
Source/Credit: Lund University | Åsa Hansdotter
Reference Number: immg011426_01
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