How a common cancer immunotherapy target might also hold the key to tackling obesity

The PD-L1 protein is a popular target for cancer immunotherapies, as tumors use it like a “brake” to dampen immune responses against them. But scientists from Germany and Ireland have evidence that the protein may also act as a protector against obesity.

PD-L1 expression on a group of immune cells called dendritic cells is a key regulator controlling inflammation in fat tissues, a hallmark of obesity. A group of researchers from the University of Erlangen-Nuremberg (FAU) and Trinity College Dublin described the discovery in a new study published in Science Translational Medicine.

The findings are relevant not only for research into treating obesity but also for cancer patients who receive PD-1/L1 checkpoint inhibitors, the researchers said.

“We now report that there are dynamic changes in effector T cells within the actual adipose tissue of obese mice after anti-PD-L1 inhibition that will impact on function of effector T cells systemically as well in the tumor environment,” which can be rich with adipose, or fat, tissue, Padraic Fallon at Trinity, a study co-corresponding author, said in an email to Fierce Biotech Research.

During the progression to obesity, the composition of immune cells in fat tissues shifts to an inflammatory state, which can contribute to the development of the condition. But the exact mechanism of the inflammatory signaling in early stages of obesity was unclear.

Given PD-L1’s role in reining in immune responses, the FAU-Trinity team removed PD-L1 in a mouse model of obesity induced by a high-fat diet. Compared with normal mice, the engineered mice became more obese and had increased insulin resistance.

As the loss of PD-L1 appeared to boost inflammatory immune activity in fat tissue, the researchers analyzed the function of PD-L1 in different immune cell types and found that it was the PD-L1 on dendritic cells that mattered in weight gain. The low level of chronic inflammation in fat tissue led to increased expression of PD-L1 on dendritic cells, as the cells tried to contain inflammation by inhibiting effector T-cell responses, the team found.

What’s more, in people with obesity, the PD-L1 expression in visceral fat was found to be correlated with the body mass index of patients.

Naturally, the team tested the effect of a PD-L1 inhibitor, which has been used to treat various cancer in people. In obese mice, animals that got an anti-PD-L1 treatment gained more weight and exhibited a worse metabolic state similar to the effects observed in genetically modified mice without PD-L1.

Noting that cancer patients usually change their diet or lose weight because of the disease, the FAU-Trinity researchers switched obese mice to a conventional diet.

As expected, the rodents started to lose weight after the switch. But, unlike the obesity-boosting effect observed in obese mice fed a high-fat diet, rodents that switched to a normal diet and were treated with anti-PD1/L1 antibody saw significantly accelerated weight loss relative to the control group. However, the faster weight loss came with a worsening of metabolic health, “suggesting a systemic inflammatory effect of [antibody] treatment in a state of low-grade inflammation during obesity,” the researchers noted.

Obesity remains an epidemic that needs more treatment options. A team of scientists in China recently proposed a low dose of the anticancer drug camptothecin could be an easily translatable candidate after showing positive results in mice. Another team found that local heat therapy also holds promise as a weight loss strategy, because it could trigger the browning of “beige fat” into an energy-burning state through the HSF1-A2B1 pathway.

Past studies have explored how an obese state may influence the treatment outcome of PD-1/L1 blockers. The new findings on PD-L1’s role in fat tissue have implications not just for patients with obesity but also cancer patients who are receiving PD-1/L1 checkpoint inhibitors, including the effects on immune response and side effects because of the modulation of immune cells in fat tissue, the FAU-Trinity researchers said. “The increased expression of PD-L1 we and others observed in adipose tissue therefore is an important and possibly overlooked factor in cancer therapy.”