Obesity is a well-known cancer risk – but is also known to increase the likelihood of immunotherapy success. A new discovery from Vanderbilt University Medical Center-led research team may explain why – and how this could lead to improved treatment for non-obese patients as well. The findings, published in Nature, reveal that obesity increases the frequency of macrophages in tumours and induces their expression of the immune checkpoint protein PD-1 – a target of cancer immunotherapies.
“Obesity is the second leading modifiable risk factor for cancer, behind only smoking, and obese individuals have a greater risk for worse outcomes. But they also can respond better to immunotherapy,” said Jeffrey Rathmell, PhD, Cornelius Vanderbilt Professor of Immunobiology and director of the Vanderbilt Center for Immunobiology. “How is it that there can be this worse outcome on one hand, but better outcome on another? That’s an interesting question.”
Postdoctoral fellow Jackie Bader, PhD, led the studies to examine the influence of obesity on cancer and to explore this “obesity paradox” – that obesity can contribute to cancer progression but also improve response to immunotherapy.
In a mouse model, the researchers found striking differences between the macrophages isolated from tumours in obese versus lean mice. While the protein PD-1 is an immunotherapy target normally thought to act on T cells, they discovered that the macrophages in tumours from obese mice expressed higher levels of PD-1, and that PD-1 acted directly on the macrophages to suppress their function.
In tumour samples from patients with kidney cancer, the researchers also found PD-1-expressing macrophages, and in human endometrial tumour biopsies from patients before and after 10% weight loss, they showed that PD-1 expression on tumour-associated macrophages decreased following weight loss.
“We were very fortunate to have collaborators that provided us with samples from the same patients before and after weight loss that reinforced the findings from our mouse models,” Bader said.
Blocking PD-1 with an immunotherapy drug in the mouse models increased tumour-associated macrophage activity, including their ability to stimulate T cells.
‘Team macrophage’
Cancer immunotherapy studies have largely focused on T cells, because they are the immune cells that can kill cancer cells, Bader and Rathmell said. But macrophages play important roles in influencing what T cells do.
“I’ve always been ‘team macrophage,’” Bader said. “Macrophages are thought of as being like a garbage truck: They clean up the mess. But they have a huge spectrum of activity to enhance the immune response, and they’re more plastic and manipulatable than other immune cells, which makes them really interesting.”
The presence of more macrophages expressing PD-1 in tumours in an obese setting provides a mechanistic explanation for the obesity paradox, Bader and Rathmell said. Increased PD-1 expression suppresses immune surveillance by macrophages, subsequently suppressing the killer T cells and allowing tumours to grow (the increased cancer risk of obesity). PD-1 blockade with immunotherapy allows the increased number of PD-1-expressing macrophages to act (the enhanced response to immunotherapy).
Currently, immune checkpoint inhibitors work in only 20–30% of patients.
“We clearly want to find ways to make immunotherapies work better, and in the obese setting, they naturally work better,” Rathmell said. “Understanding how these processes are working biologically may give us clues about how to improve immunotherapy in general.”
The findings also suggest that examining levels of PD-1-expressing tumour macrophages may help identify patients who will respond better to immunotherapy.
“It could be that the greater the proportion of PD-1-expressing macrophages a tumour has, the better the response to immunotherapy will be,” Rathmell said.
Source: Vanderbilt University
