How Cancer Hides Pain

Cancer pain

Melanoma cells use a protein called PD-L1 to suppress pain, according to a new mouse study. Image credit: NCI Center for Cancer Research.

Cancer is often painful, but some types, such as melanomas (skin tumors), are usually pain-free, at least before they spread to other parts of the body. Now, Ru-Rong Ji, Duke University, Durham, US, and colleagues might have found one reason why.

The researchers take a careful look at mice experimentally injected with melanoma cells. Like other cancer cells, these produce a protein that suppresses the immune system, called PD-L1. Ji and colleagues now show that PD-L1 also decreases the activity of pain-sensing neurons, ultimately masking the pain that would otherwise arise with cancer.

But tumor cells are not the only ones that churn out PD-L1. The investigators also found the protein in a number of healthy tissues. And, blocking the activity of PD-L1 in healthy mice caused harmless touch to trigger pain.

“This paper is meaningful,” says Brian Schmidt, New York University, US, a cancer pain researcher and surgical oncologist who was not involved in the study. “It has not been demonstrated previously that PD-L1 is analgesic [pain-relieving], and PD-L1 has not been looked at in the setting of cancer pain.”

The results point to the possibility that immune therapies designed to treat cancer could have unintended effects on pain.

“The hottest drugs out there for many cancers, including melanoma, are those for PD-L1 and PD1 [the protein to which PD-L1 attaches],” says Schmidt. “So you can imagine: If we’re going to be antagonizing that system, are we going to see increasing levels of pain?”

The paper was published online May 22 in the journal Nature Neuroscience.

“A new painkiller”
Researchers have long known that tumor cells make PD-L1, but previous studies have largely focused on how the protein affects the immune system, said Ji. “Cancer is smart. It can suppress an immune response so that it can grow without much detection.”

As Ji also knew from animal studies, immune responses can lead to changes in pain levels, so he asked, Could PD-L1 control pain as well?

To find out, lead authors Gang Chen and Yo Ho Kim, along with their colleagues, injected formalin—a chemical solution that triggers inflammation and pain—into the paws of normal mice; this is a common technique used to study pain in animals. They then followed that with an injection of PD-L1 or an innocuous salt-water solution (used as a control).

Compared to the salt-water solution, PD-L1 reduced how long the mice spontaneously licked the inflamed paw and flinched, two behaviors thought to indicate the presence of pain in animals. In other words, PD-L1 relieved pain.

When the researchers instead prevented PD-L1 from attaching to PD1 in normal mice using nivolumab, a US Food and Drug Administration (FDA)-approved drug for cancer, the animals withdrew their paws to the slightest pressure. This response to light touch as if it were painful is known as allodynia.

“We’ve discovered a new painkiller,” said Ji. “Even in the absence of a tumor, normal tissues can produce PD-L1.”

Such tissues are surprisingly diverse. The researchers could detect PD-L1 at varying levels in the skin, sciatic nerve, pain-sensing neurons, spinal cord, brain, liver, spleen, and kidney.

Painless cancer
To explore whether PD-L1 could explain why melanoma is usually not painful, the researchers once again blocked the protein’s actions with nivolumab, but this time in mice injected with melanoma cells. Remarkably, these animals rapidly showed telltale signs of pain–not only did they spontaneously flinch and lick themselves, but they also developed allodynia.

To Ji, “this indicates that there is cancer pain with melanoma, but it’s masked by PD-L1.” Through additional experiments, it seemed that this effect depended on pain-sensing neurons, which directly responded to the protein.

At the moment, it’s unclear what the findings mean for cancer patients treated with drugs that interfere with PD-L1 or PD-1. Schmidt himself has not heard patients for whom he’s prescribed these drugs complain that they cause pain. And yet, “Ji’s group shows that if you block PD-1 with nivolumab, you should get pain,” he says.

While there have been scattered reports of pain in those taking nivolumab, “there’s no careful research on this topic,” says Ji. He is now collaborating with physicians to address this issue.

To read about the research in more detail, see the related Pain Research Forum news story here.

Matthew Soleiman is a science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman