Age shapes melanoma progression and immune response

Cancer risk increases with age and is often more aggressive and difficult to treat in older adults. However, fewer than 10% of mouse studies use aged animals, with most relying on mice roughly equivalent to humans in their early 20s. This discrepancy is one potential reason so many cancer drugs that show promise in preclinical models go on to fail in human trials.

New research from Fox Chase Cancer Center, presented at the American Association for Cancer Research annual meeting, suggests melanoma behaves differently with age. The data showed cancer spread was the lowest in young mice, peaked in middle‑aged mice, and declined in very old mice.

"The vast majority of studies are done in these very young mice that have a healthy and intact immune system," said Mitchell Fane, PhD, a cancer biologist who specializes in aging and cancer, and lead investigator of the study. "Right now, it's easy to personalize care for someone who's young and fit, who's potentially not going to experience as many toxicities; understanding how therapies affect older patients would give us more and better treatment options."

Fane and his colleagues suggest that a key factor behind their findings involves a specific group of immune cells called gamma delta (γδ) T cells, which act like early warning guards that help prevent cancer from spreading. Young and very old mice had more of these protective immune cells, and their cancer was more likely to stay dormant or spread less. Middle‑aged mice had fewer γδ T cells, and their melanoma was far more likely to spread to organs like the lungs and liver.

The study also showed that melanoma cells themselves can actively weaken the immune system as animals age. In middle‑aged mice, melanoma released certain molecules that shut down or exhaust γδ T cells, allowing previously quiet cancer cells to "wake up" and spread aggressively.

Notably, when researchers removed γδ T cells from young and very old mice, melanoma spread increased, suggesting these immune cells normally help keep the cancer in check. By contrast, blocking immune‑suppressing signals restored immune protection and reduced cancer spread, but only in middle‑aged mice.

A more inclusive mouse model

One reason few studies use older mice is that young mice are cheaper and faster to obtain. Mice must be bred and cared for about 18 to 24 months before they are old enough for aged‑mouse models.

Fane and his colleague Yash Chabra, PhD, both Assistant Professors in the Cancer Signaling and Microenvironment Research Program, helped establish an aged mouse facility at Fox Chase. Together they are providing researchers with access to better models for how cancer behaves in older patients.

"Now we have a facility with established aged mouse colonies, which lowers the cost and time barriers to aging research," he said. "It allows us to tell colleagues, 'Your model is interesting, why not test it in aged mice?'"

Personalizing care for older patients

Better understanding the role of aging in cancer is a key step to developing better treatments for older patients. Fane's lab is also interested in how the link between cancer risk and age is not linear.

While risk increases steadily as people age, it abruptly decreases after ages 80-85. We want to explain the mechanism of why very old patients are getting less cancer, but middle-aged patients are getting more."

Mitchell Fane, PhD, cancer biologist