A team of researchers at the University of Southern California has developed a method to expand a key population of blood-forming progenitor cells in the laboratory while preserving their identity and function, overcoming a longstanding barrier in hematology and opening new possibilities for cancer immunotherapy.
The study, published in Cell, describes how investigators generated large numbers of granulocyte-monocyte progenitors (GMPs)—immune precursor cells that give rise to macrophages, monocytes, and neutrophils—using a culture system that enables these cells to self-renew in vitro. The work not only challenges conventional assumptions about hematopoietic progenitor biology but also provides a potentially scalable platform for engineering immune cells designed to attack cancer.
“This is the first time we can pick single progenitor cells and expand them in large quantities without differentiation,” said senior author Qi-Long Ying, PhD, professor of stem cell biology at USC. “They retain the original identity.”
The achievement addresses a problem that has frustrated researchers for decades. Although hematopoietic stem cells and their descendants have been extensively studied, scientists have struggled to maintain specific blood-forming progenitor populations in culture over long periods without the cells differentiating into mature immune cells.
Ying said the project grew out of his laboratory’s experience working with embryonic stem cells, which can be maintained indefinitely in culture. He reasoned that if embryonic stem cells could be expanded long term, similar approaches might eventually be developed for stem and progenitor cells found in bone marrow.
After years of experimentation, the researchers established culture conditions that selectively support GMPs, a progenitor population responsible for generating several innate immune cell types involved in recognizing and destroying abnormal cells.
Challenging a longstanding paradigm
According to co-author Daniel McKim, PhD, one of the most surprising findings was not simply the ability to expand GMPs but the demonstration that these progenitor cells could undergo extensive self-renewal in vitro.
“The prevailing theory has been that hematopoietic progenitors are short-lived intermediate cells that are incapable of self-renewal,” McKim said. “One of the distinctions between hematopoietic stem cells and progenitors is the belief that these cells are not able to self-renew. What we found is that under the right conditions, they can.”
The researchers emphasize that the self-renewal phenomenon occurs in culture. Once transplanted back into animals, the GMPs behave like normal progenitor cells, producing downstream immune populations before eventually becoming depleted.
Still, the ability to generate vast numbers of GMPs in vitro represents a significant technical advance. The investigators report expansion levels approaching eight orders of magnitude while maintaining the cells’ progenitor characteristics.
Building better cell therapies
Beyond the basic biology, the researchers see major implications for cancer immunotherapy.
Current cellular immunotherapies are dominated by CAR T-cell approaches, which have transformed treatment for several blood cancers but have shown more limited success against solid tumors. Investigators have long been interested in developing therapies based on macrophages and other innate immune cells because those cells naturally infiltrate tumors and can reshape the tumor microenvironment.
However, translating those concepts into viable therapies has proven difficult. Mature macrophages and monocytes are challenging to genetically engineer, difficult to manufacture at scale, and often fail to persist after infusion.
The newly expanded GMPs may provide a solution. Because the progenitor cells can be generated in large numbers and genetically modified before transplantation, they offer a renewable source of tumor-fighting immune cells.
“In our body these cells are very rare,” Ying said. “The mature cells cannot grow, and it is very challenging to genetically modify them. Now we have progenitor cells that can be expanded long-term in large quantities, and we can easily genetically modify them. That makes everything possible.”
The team engineered both mouse and human GMPs with chimeric antigen receptors (CARs) and evaluated them in mouse models. Unlike mature macrophages, which often become trapped in organs such as the lungs and liver after infusion, the progenitor cells distributed broadly throughout the body and engrafted within the bone marrow.
Once established, the cells generated populations of macrophages and monocytes capable of infiltrating tumors.
McKim noted that this approach may overcome several limitations that have hindered macrophage-based immunotherapies. “One of the big issues has been that it’s hard to engineer these cells, and when you put them back into the body they don’t get where they need to go,” he said. “The progenitors solve both problems. They’re easy to engineer, and they expand after transplantation.”
Implications for solid tumors
The researchers believe progenitor-derived innate immune therapies may offer advantages in solid tumors, where CAR T-cell approaches have struggled.
Tumors often create highly suppressive microenvironments that limit T-cell activity. Macrophages and related innate immune cells, by contrast, naturally migrate into tumors and can help stimulate broader immune responses.
“Monocytes and macrophages love going into tumors,” McKim said. “They can kill tumor cells themselves, but they can also help generate a natural antitumor immune response by the host.” That capability could prove particularly important in cancers that evade treatment by losing specific target antigens, a common mechanism of resistance to CAR T-cell therapy.
Although the work remains preclinical, the investigators believe the platform could eventually support a wide range of immune-engineering applications beyond cancer.
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