A research team led by Vanderbilt University Medical Center has uncovered an unexpected role for immune system cells known as macrophages in the complex relationship between obesity and cancer. Their study, published on June 12 in the journal Nature, reveals that obesity elevates the presence of macrophages in tumors and triggers their production of the immune checkpoint protein PD-1 (1^✔ ✔Trusted Source
Obesity-cancer connection discovery suggests strategies for improving immunotherapy

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Deciphering the Obesity Paradox: Impact on Cancer and Immunotherapy

This discovery sheds light on how obesity can heighten cancer susceptibility while also boosting responses to cancer immunotherapies. Furthermore, it offers insights into potential avenues for enhancing immunotherapy effectiveness and identifying patients most likely to benefit from such treatments.

“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 tumors 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 tumors from obese mice expressed higher levels of PD-1, and that PD-1 acted directly on the macrophages to suppress their function.

Role of Macrophages in Cancer and Immunotherapy

In tumor samples from patients with kidney cancer, the researchers also found PD-1-expressing macrophages, and in human endometrial tumor biopsies from patients before and after 10% weight loss, they showed that PD-1 expression on tumor-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 tumor-associated macrophage activity, including their ability to stimulate T cells.

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 tumors 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 — and subsequently suppresses the killer T cells — allowing tumors 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 tumor 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 tumor has, the better the response to immunotherapy will be,” Rathmell said.

Reference:

1. Obesity-cancer connection discovery suggests strategies for improving immunotherapy – (https://news.vumc.org/2024/06/12/obesity-cancer-connection-discovery-suggests-strategies-for-improving-immunotherapy/)

Source-Medindia