Scientists from Vanderbilt University Medical Center recently discovered a unique connection between obesity and cancer – immune cells called macrophages.
I mean, we know that obesity is linked to the occurrence of cancer, but obese individuals respond better to immunotherapy. We could never understand why. This is the obesity code that scientists have been confused about. That changes now.
A little context: Macrophages are immune cells (white blood cells) that kill enemy cells (for instance, microorganisms) attacking the body. You could look at that as garbage trucks that clean the mess. They are usually one of our first lines of defence, after the physical barrier, i.e. our skin. They also help T cells fight diseases and are often a hot topic in immunology and disease research, cause of their special roles.
The Obesity Code: Understanding Their Research
Now, to understand what the scientists at Vanderbilt found, you should know that obesity is linked to your DNA, which is linked to cancer. Obese people are at risk of getting cancer, it’s a given. They face worse outcomes, however, tend to respond better to immunotherapy (a way to cure cancer). And this is somehow related to macrophages, our immune system.
The research found that obesity increases the frequency of macrophages in tumours and leads to the expression of an immune checkpoint protein PD-1 (this is a checkpoint molecule that helps cells divide in the right way). This means, the more obese an individual is, the more PD-1 expressing macrophages in their body. In other words, if PD-1 is expressed too high, the cells might become cancerous. As a part of immunotherapy, scientists target the PD-1-expressing macrophages and thereby block the cell cycle in cancerous cells. And thus, obesity favors the immunotherapy treatment by favouring PD-1-expressing cells.
What is interesting is that obesity is the second leading modifiable risk factor for cancer, after smoking. This means that in the case of obese individuals, blocking the PD-1-expressing cells would be more effective, thereby making obese people better targets for immunotherapy. This also means that obesity is a boon for people with cancer who are being treated with immunotherapy.
Jeffrey Rathmell, PhD, Cornelius Vanderbilt Professor of Immunobiology and director of the Vanderbilt Center for Immunobiology, asks, “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 major differences between the macrophages isolated from tumors in obese versus lean mice. This simply means that the two mice differ in the PD-1 expressing macrophages in their tumors. PD-1 directly acts on macrophages to kill it.
Moreover, 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 with weight loss, the PD-1 expressing macrophages also decreased in number. This simply means that PD-1 could be a great target for killing cancer cells, since that’s where they are being highly expressed. This is where the obesity code cracked better.
Blocking PD-1 with an immunotherapy drug in the mouse models increased tumour-associated macrophage activity, including their ability to wake up T cells to do their usual function in cancer.
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 obesity code findings also suggest that examining levels of PD-1-expressing tumor macrophages may help identify patients who will respond better to immunotherapy.
Also, read about if we have a cure for cancer yet here.
Stay tuned for more such research!
