Immunotherapies work by unleashing the immune system to fight cancer, but they are only effective in about 20 percent of cases, prompting many patients to wonder if they are worth the risk. Plus, they can carry severe side effects.
A new study from Duke University shows that there may be a quick and simple way to predict which cancer patients can benefit from immunotherapy treatments.
The researchers showed that a molecule called PD-L1, which is blocked by the popular immunotherapy drug nivolumab, acts not only on immune cells but also on the nerve cells that signal pain. That insight could lead to a simple test that measures subtle differences in pain sensitivity to gauge whether the body is responding to treatment, or not.
“Cancer cells are smart. We already knew that they produced PD-L1 to suppress the immune system,” said senior study author Ru-Rong Ji, Ph.D., professor of anesthesiology and neurobiology at Duke University School of Medicine. “But there’s another defense system at play as well, and that is pain. We showed that this well-known molecule can mask pain, so that cancers can grow without setting off any alarms before metastasis.”
Ji and his group recently noticed that mouse models of melanoma didn’t show the typical signs of pain that he observed in mice with other kinds of cancer. He knew that melanoma cells could produce a molecule called PD-L1, which latched onto a receptor called PD-1 on the surface of white blood cells, effectively putting the brakes on the immune response.
His team treated mice with nivolumab, a drug that prevents PD-L1 from binding to PD-1. Then they poked the animals’ hind paws with a calibrated filament and measured how much force it took for them to withdraw their hind paws. They found that the mice responded to much lower forces than before treatment, indicating they had become more sensitive to pain. In addition, they also found that nivolumab caused spontaneous pain in mice with melanoma, which made them tend to their affected hindpaws like never before.
Next, the researchers performed the opposite experiment. They injected PD-L1 — the pain-masking factor in this equation — into the hind paws or spinal cord of mouse models of three different kinds of pain — inflammatory, neuropathic and bone cancer pain. In every case, the injections of PD-L1 had an analgesic effect, deadening the mice’s sensitivity to pain.
“The effect was surprisingly fast,” said Ji. “We saw a reduction of pain in under half an hour.”
Ji believes the finding could potentially lead to new treatments for pain, as well as new ways to predict the efficacy of already existing treatments based on PD-1 and PD-L1. “The response to cancer drugs can take a long time, weeks to months,” he said. “The response to pain happens in minutes to hours.”
The findings were published in the May 22 issue of Nature Neuroscience.