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SciImmunol: Reprogramming technique can transform fibroblasts into antigen-presenting cells

For the first time, a team of researchers at Lund University in Sweden has succeeded in reprogramming mouse and human skin cells into immune cells called dendritic cells. The process is rapid and effective and represents a seminal contribution to the direct reprogramming of induced immunity. Importantly, the discovery opens up the possibility of developing novel dendritic cell-based immunotherapies against cancer.

What we call dendritic cells are the sentinels of the immune system. Their task is to scan our tissues for foreign particles, such as bacteria, viruses or cancer cells, and engulf them. They then break the particles down into smaller fragments called antigens and present them on the surface of the immune system's killer cells (T cells). In this way, killer cells can learn about the infectious agents and cancer cells they want to search for and kill.

Because of these key features, dendritic cell-based strategies have been tested to treat cancer patients. However, cancer can affect dendritic cells in such a way that they are lost or become dysfunctional. Therefore, we need to find new ways to generate dendritic cells for each patient. Now, for the first time, a research group in Lund has succeeded in obtaining dendritic cells through a process called direct reprogramming. They have identified three essential proteins (PU.1, IRF8 and BATF3) that are required to change the identity of mouse cells enough to make them dendritic cells. They also demonstrated that the same protein mixture reprogrammed human skin-derived cells into dendritic cells. The study is now published as a cover article in the journal Science Immunology.

"From tissue sections removed from the skin, we can culture millions of cells and reprogram them into dendritic cells in a process that takes only nine days," said Filipe Pereira, head of the research team in charge of the study.

“Our research shows that, The reprogrammed cells are capable of working in the same way as' natural' Dendritic cells efficiently capture antigens and present them to killer cells in the same way。” Researchers can even introduce cells into an organism before, By providing them with the correct antigen in the test tube, Directing Induced Dendritic Cells to Specific Targets。 This discovery opens up future possibilities for the development of new strategies for immunotherapy against solid tumors and blood cancers, Beyond the currently available treatments。

"This is an excellent opportunity to merge the fields of cell reprogramming and cancer immunotherapy. From a therapeutic point of view, the use of direct cell reprogramming to generate dendritic cells is very attractive: our study could potentially be used in the clinic to generate patient-specific dendritic cells," according to Filipe Pereira.

Cancer immunotherapy uses the cellular components of the body's immune system to fight cancer and was awarded the Nobel Prize in Physiology or Medicine this year. By using reprogrammed dendritic cells, there is a lower likelihood of organism rejection because these cells can be generated from the skin of each individual patient.

"Tumors often undergo a large number of mutations and develop into heterogeneous entities, which makes it more difficult for the immune system to recognize them as a threat. From a more creative perspective, we now want to explore the developmental process of dendritic cell reprogramming. Cancer Gene Therapy. Our goal is to inject the three reprogrammed proteins directly into the tumor, forcing it to present its own tumor-specific antigens. This activates killer cells against tumor cells and may lead to their elimination. We named this concept TrojanDC in analogy with Homero's Trojan horse. The enormous potential of this technology for cancer treatment has led us to start a new company with Lund University to develop the concept into a product that will hopefully one day reach cancer patients," said Filip Pereira.

"In addition, our study opens up the possibility of reprogramming other dendritic cell subtypes to take advantage of their unique functional characteristics. A better understanding of the mechanisms that determine the identity of immune sentinels and how to use this knowledge to reprogram other cell types into dendritic cells could make these patient-specific cells useful in the clinic," concludes Filipe Pereira.

Information source: A code for reprogramming immune sentinels

Original source:Fábio F. Rosa et al. Direct reprogramming of fibroblasts into antigen-presenting dendritic cells. Science Immunology, 2018; 3 (30): eaau4292 DOI: 10.1126/sciimmunol.aau4292

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