Study identifies a previously unknown role of PD-L1 in cancer

Immunotherapy has emerged as an important treatment for cancer patients. It uses substances that restore or enhance the immune system's natural ability to fight cancer. However, clinicians note a variety of side effects such as skin rashes, allergic reactions, endocrine disorders, and heart damage that may accompany immunotherapy. Data show that immunotherapy agents work for only around a fifth of patients.

A team led by Prof. Ru-Rong Ji at Duke University Medical Center has found a simple way to determine which cancer patients are likely to benefit from immunotherapy. Their study, published online 22 May 2017 in Nature Neuroscience, shows that PD-L1 (programmed death-ligand 1) acts not only on immune cells but also on neurons that signal pain.

PD-L1 is a ligand of PD-1 (programmed cell death protein 1), a cell surface receptor that plays a key role in down-regulating the immune system. PD-L1 and PD-1 belong to the family of immune checkpoint proteins, which can limit the development of the T cell response. Blocking the PD-L1/PD-1 pathway represents a strategy for immunotherapy. For example, a common cancer drug -- nivolumab-- works as checkpoint inhibitor that blocks the PD-L1/PD-1 interaction.

Cancer cells can escape the body defense mechanisms in different ways. Multiple cancer types, such as melanoma, manage to inhibit the immune system by generating PD-L1. The feeling of pain is another defense mechanism that tells a person to protect the injured or diseased area. Generally, when cancer progresses to an aggressive form, cancer cells will produce a large number of pain-inducing chemicals that stimulate pain-sensing neurons. In cancer patients, the pain can be unbearable.

While studying pain, Ji's team surprisingly found that mice with melanoma did not exhibit signs of pain seen in mice with other types of cancer. The researchers asked if there was a link between the expression of PD-L1 by melanoma cells and pain insensitivity observed in these animals. To address this question, they treated mice with nivolumab and used a test to evaluate their pain sensitivity. Results showed that treatment with nivolumab made mice more sensitive to pain as well as triggered spontaneous pain in mice with melanoma. In contrast, injection of PD-L1 reduced pain sensitivity in mouse models of inflammatory, neuropathic or bone cancer pain.

The team then further explored this function of PD-L1 by examining sensory neurons at the dorsal root ganglion and discovered that PD-L1 potently suppressed nociceptive neuron excitability. Together, these data suggest that the checkpoint protein PD-L1 may act as a pain inhibitor and a neuromodulator. The discovery may aid in the development of new painkillers as well as new ways to predict the effectiveness of immunotherapy agents that target the PD-L1/PD-1 pathway.
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