We might be able to manufacture millions to billions of infection- and cancer-fighting dendritic cells—if only we knew, in detail, how they are produced in the body. We have known for decades that dendritic cell numbers increase in response to a hormone called Flt3L. But exactly how Flt3L spurs production has remained unclear.

Now, thanks to new research from the Walter and Eliza Hall Institute (WEHI), we have a better understanding of how dendritic cells develop. WEHI scientists say that dendritic cells arise through “clonal tuning,” a process that could be exploited to improve immunotherapy treatments for patients.

The new research has been summarized in an article (“Single-cell analyses reveal the clonal and molecular etiology of Flt3L-induced emergency dendritic cell development”) that appeared March 1 in Nature Cell Biology. The article describes how WEHI researchers, led by Shalin H. Naik, PhD, laboratory head, WEHI, used single-cell technology to identify Flt3L-responsive hematopoietic stem cells (HSPCs). The article also reveals how Flt3L mediates the production of type 1 conventional dendritic cells (cDC1s) in response to stress conditions.

“Using cellular barcoding, we demonstrate this occurs through selective clonal expansion of HSPCs that are primed to produce cDC1s and not through activation of cDC1 fate by other HSPCs,” the article’s authors wrote. “In particular, multi/oligo-potent clones selectively amplify their cDC1 output, without compromising the production of other lineages, via a process we term tuning.”

The “barcoding” technique involves the insertion of short synthetic DNA sequences, or barcodes, into cells. “[Through the use] of barcoding, we were able to determine which cells produced dendritic cells in preclinical models,” Naik said. “As a result of this research, we now better understand the actions of the Flt3L hormone that is currently used in cancer immunotherapy trials, and how it naturally helps the body fight cancer and infection.”

The scientists also used Divi-Seq—a single-cell multiomics method that incorporates tracking of cell division with immunophenotyping and transcriptomic analysis—to simultaneously profile the division history, surface phenotype, and transcriptome of individual HSPCs.

“We discover that Flt3L-responsive HSPCs maintain a proliferative ‘early progenitor’-like state, leading to the selective expansion of multiple transitional cDC1-primed progenitor stages that are marked by Irf8 expression,” the authors of the Nature Cell Biology article reported. “These findings define the mechanistic action of Flt3L through clonal tuning, which has important implications for other models of ‘emergency’ hematopoiesis.”

This research answers a 50-year-long question as to what causes a stem cell to react in response to immense stress, such as infection or inflammation. “We have known that the Flt3L hormone increases the number of dendritic cells for decades, but now there is a focus on applying this knowledge to cancer immunotherapy and potentially to infection immunotherapy as well,” Naik said.

Dendritic cells are immune cells that activate “killer” T cells, which are vital for clearing viral infections, such as COVID-19, but also for triggering a response to cancers such as melanoma and bowel cancer. When dendritic cell numbers are increased through the influence of the Flt3L hormone, the immune system is better able to fight off cancer and infection.

“There is one type of dendritic cell that the body uses to fight some infections and cancer,” Naik explained. “The Flt3L hormone increases numbers of this particular dendritic cell.”

Now that the actions of the Flt3L hormone are better understood, Naik continued, it may now be possible to improve immunotherapy techniques. “The next stage in our research,” he declared, “is to create ‘dendritic cell factories’ using our new knowledge, to produce millions to billions of these infection-fighting cells and then use those in immunotherapy treatments.

“These findings are a vital first step to improving immunotherapy treatments for patients, to help them better fight cancer and infection.”

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