The immune system cells known as macrophages are now known to play an unexpected role in the complex link between obesity and cancer, according to a research team led by Vanderbilt University Medical Center. The team’s findings offer a detailed explanation for how obesity can contribute to both an increased risk of cancer and improved responses to immunotherapy. Obesity is known to increase the presence of macrophages in tumors and also leads to an increase in their expression of the immune checkpoint protein P.The article discusses how obesity can impact cancer immunotherapies. According to the research published in Nature, the study provides a detailed explanation of how obesity can increase the risk of cancer and enhance the body’s response to immunotherapy. This information could help in developing strategies to improve immunotherapy and identify the patients who are most likely to benefit from the treatment. Jeffrey Rathmell, PhD, Cornelius Vanderbilt Professor of Immun, stated that obesity is the second leading risk factor for cancer and can result in worse outcomes for patients. However, it also found that obese individuals may respond better to immunotherapy.obesity and its impact on cancer outcomes is a fascinating topic,” says the article by Dr. Mark Boothby, a professor of obiology and director of the Vanderbilt Center for Immunobiology. The article questions how obesity can lead to worse cancer outcomes in some cases, but also lead to better outcomes in others.
The studies conducted by postdoctoral fellow Jackie Bader, PhD, focused on exploring the relationship between obesity and cancer. They aimed to understand the “obesity paradox,” which suggests that obesity can both contribute to cancer progression and improve the body’s response to immunotherapy.
Using a mouse model, the researchers observed significant differences in the macrophages extracted from tumors in obese mice compared to those in lean mice. Specifically, they found that the protein PD-1, which is a target for immunotherapy, functions differently in obese mice than in lean mice.The researchers discovered that in tumors from obese mice, the macrophages had higher levels of PD-1, which directly suppressed their function. They also found PD-1-expressing macrophages in tumor samples from patients with kidney cancer. In human endometrial tumor biopsies from patients who had lost 10% of their weight, the researchers observed a decrease in PD-1 expression on tumor-associated macrophages. Collaborators provided samples from the same patients before and after weight loss, which supported these findings.our mouse models,” said Bader.
When an immunotherapy drug was used to block PD-1 in the mouse models, it led to an increase in tumor-associated macrophage activity. This included their ability to stimulate T cells.
Bader and Rathmell explained that cancer immunotherapy studies have typically focused on T cells, as they are the immune cells capable of killing cancer cells. However, macrophages also play a crucial role in influencing the actions of T cells.
“I’ve always been ‘team macrophage,'” Bader said. “Macrophages are often likened to a garbage truck: they clean up the mess. However, they have a wide range of activity that can enhance the response is a fascinating area of study, particularly in the context of obesity. Macrophages are particularly interesting because they are more adaptable and alterable than other immune cells. This means that they can play a significant role in the immune response.
A study found that in obese individuals, there are more macrophages expressing PD-1 in tumors. This finding helps to explain the obesity paradox. The increase in PD-1 expression by macrophages suppresses immune surveillance and subsequently suppresses killer T cells, leading to tumor growth and an increased risk of cancer in obese individuals. However, PD-1 blockade with immunotherapy can enhance the response to treatment by allowing the increased number of PD-1-expressing macrophages to act.
There is ongoing research into the immune response in obesity, and it is an area of great interest and potential for further understanding and treatment development.Checkpoint inhibitors only work in a relatively small percentage of patients, with estimates ranging from 20% to 30%. “We are eager to discover ways to enhance the effectiveness of immunotherapies, and in the case of obesity, they naturally perform better,” Rathmell stated. “Understanding the biological mechanisms behind these processes may provide insights into how to improve immunotherapy overall.”
The results also indicate that evaluating the levels of PD-1-expressing tumor macrophages could help identify patients who are more likely to respond well to immunotherapy. “It’s possible that the higher the proportion of PD-1-expressing macrophages in a tumor, the better the response to immunotherapy will be,” Rathmell suggested.
The study received funding from various sources including the National Institutes of Health, the American Association for Cancer Research, and the Vanderbilt-Incyte Alliance. Specifically, the grants received were K00CA234920, F31CA261049, F30CA239367, F30CA247202, K00CA253718, F99CA274695, T32DK007314, R01CA217987, T32GM007753, K08CA241351, R01CA238263, R01DK105550, T32GM007347, K12 CA090625, and T32DK101003.
