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Modified immune cells issue alert when detecting cancer in mice

Mar 20, 2019

March 19, 2019, New York — Immune cells equipped to detect and report tumors could open a new approach to diagnosing cancer, according to a study led by Sanjiv Gambhir, a Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research at Stanford University. The study, done in mice, involved modifying a class of immune cells known as macrophages to search the body for cancer and send a signal detected in blood or urine when they stumbled on such trouble. A paper detailing its findings of the study was published online March 18 in Nature Biotechnology.

“We’ve been after early cancer diagnostics for years, but this time, we came at it from another angle,” said Sanjiv “Sam” Gambhir, who is also professor and chair of radiology at the Stanford University School of Medicine and director of the Canary Center at Stanford for Cancer Early Detection. “We said, if nature doesn't give you sufficient signal that cancer is present, can we force the body to make one?”

Gambhir notes that this is possibly the first in-animal example of “immunodiagnostics,” which seeks to repurpose the body’s own cells to report disease or cellular damage. The technique, he said, may also be tailored to flag other disorders, such as multiple sclerosis or chronic inflammation.

Macrophages naturally patrol the body for signs of danger, including infected and cancerous cells, and certain genes are known to turn on in macrophages when they come into contact with the tumor environment.

Gambhir and his team repurposed the gene promoters—signature DNA sequences that mark the start of a gene—that perk up when macrophages detect a suspicious cell to initiate expression of a foreign gene, Gaussia luciferase, whose product generates a luminescent signal. “So the idea is, we pick a gene that turns on when a macrophage senses a tumor cell, we link that gene’s promoter to Gaussia luciferase and, finally, we integrate it into the macrophages,” Gambhir explained.

His team tested the engineered macrophages in a mouse model of breast cancer and were able to detect tumors just 4 millimeters in diameter, reading the signal in a vial of blood or urine. Because such tumors are so small, they do not produce enough circulating DNA to reliably show up in liquid biopsies, which are currently being developed for cancer diagnostics. Similarly, PET scans, a standard, image-based cancer detection method, are only sensitive enough to find tumors 8 millimeters in diameter.

Although the luminescent vial in this novel approach likely reveals the presence of cancer, it can’t provide a definitive diagnosis at this point in the development of the technique, Gambhir said. Macrophages activate certain sets of genes in response to a handful of worrisome phenomena, like tumors or wounds. Other tests would then need to be done to confirm that the signal has been triggered by a cancerous target.

Gambhir notes that logical circuitry could be built into the macrophages using tools of modern synthetic biology to more specifically detect a given environment. Further, in addition to the signal generated in blood and urine, the macrophages could be imaged through the activation of an imaging reporter and so used to locate the site of a tumor. Finally, the approaches developed in this study are not limited to macrophages and can be extended to engineer other types of immune cells.

The Stanford Medicine release from which this summary is derived can be found here.