Genetically modifying myeloid cells to produce IL12 can overcome immune suppression. These cells boost immune cell numbers in the lungs of mice with metastasizing tumors and reverse gene expression patterns associated with immunosuppression. The cells can also extend survival in mice that have had surgery to remove a primary tumor.
Myeloid cells engineered to produce IL12 restore antitumor immunity in mice, a recent study reveals (Cell 2021;184:2033–52). The cells curbed metastasis, shrank primary tumors, and increased survival, and scientists now plan to test them in clinical trials.
Myeloid cells can be powerful immune suppressors, infiltrating and protecting tumors. They accumulate at premetastatic niches, the future locations of metastases. In mice and possibly in humans, tumors prepare these sites for colonization by releasing exosomes, growth factors, and cytokines that make the local environment conducive to the survival of new cancer cells. Rosandra Kaplan, MD, of the NCI, and colleagues suspected that myeloid cells also help ready premetastatic niches by inducing an immunosuppressive milieu.
To test that idea, the researchers injected mice with rhabdomyosarcoma cells, which metastasize to the lungs. The team then analyzed lung tissue from before and just after metastasis began. They found that the number of myeloid cells increased by about 5.5 times within 22 days. The immune cell profile also changed, with a steep decline in the number of CD4+ T cells. When the scientists performed RNA sequencing on the rodents' lung tissue, they detected increased expression of many genes that foster immune suppression, including S100a8 and S100a9, which encode calcium-binding proteins that inhibit inflammation. The pattern of gene expression changes indicated that pathways promoting immune suppression were dialed up, whereas pathways that inhibit tumor growth, such as the liver X receptor pathway, were downregulated.
Kaplan and her team realized they might exploit myeloid cells. “They are so effectively homing to tumors,” she says. The scientists engineered the cells to release IL12, which spurs a variety of antitumor effects, and infused them into mice. The immunosuppressive environment changed: The number of natural killer cells, T cells, and dendritic cells rose dramatically. The gene activity pattern in the animals' lungs also shifted. Expression of genes involved in antigen presentation and T-cell receptor signaling increased, and expression of genes that promote immune suppression decreased.
In a series of experiments, the researchers also determined that the cells—given alone or with surgery, chemotherapy, or genetically modified T cells—increased survival in mice with tumors. For instance, in one experiment the researchers gave the animals the genetically altered cells and then surgically removed their primary tumors. Morethan 80% of the rodents were alive 400 days later, whereas none of the control mice, which had only surgery, lived longer than 125 days. In these experiments, the genetically altered cells not only reduced metastatic burden, but also shrank primary tumors.
Kaplan and her colleagues hope to test the approach in a clinical trial.
“To use the myeloid cells as a Trojan horse is a fantastic idea,” says Maciej Markiewski, MD, PhD, of the Texas Tech University Health Sciences Center in Abilene. “This is a brilliant concept—and it could be a trailblazer.”
Systemic IL12 has been tested against cancer, but it proved toxic. “Here, you can reduce the dose of IL12 and get it to the spot where metastasis will take place,” says David Lyden, MD, PhD, of Weill Cornell Medicine in New York, NY. The approach might also help prevent metastasis, he says.
Whether premetastatic niches form in people remains controversial, however. Some researchers, including James Talmadge, PhD, of the University of Nebraska Medical Center in Omaha, argue that the niche is a rodent artifact. Still, he says, Kaplan and colleagues may be on to something. “The premetastatic niche is probably not relevant, but the approach could still work,” he says. “They are seeing therapeutic activity.” –Mitch Leslie
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