Obesity is the biggest preventable cause of cancer after smoking, but strangely enough, immunotherapy works better in obese cancer patients than in people of a healthy weight. Macrophages probably have something to do with this.
Lead researcher Jeffrey Rathmell from the US Vanderbilt University tells to Scientias.nl about the intriguing obesity paradox when it comes to the development of cancer and its control via immunotherapy. Obesity causes the number of macrophages in the tumors to be higher than in people with a lower BMI. The protein PD-1, which is part of a macrophage, also tends to play the role of ‘checkpoint’ more often in obese people. And that is precisely an important target of immunotherapies in the form of checkpoint inhibitors.
Seven times more likely to develop uterine cancer
Rathmell’s team first listed which types of cancer are more common in obese people. “How much higher the risk of cancer is for obese patients depends on the type of cancer,” says the researcher. “It National Cancer Institute has determined that there are thirteen cancers linked to obesity. The highest risk applies to endometrial cancer, with a 600 percent greater risk in severe obesity. Breast, pancreatic and colon cancer are about 50 percent more common in obese people. Across the board, obesity is the biggest risk factor for the development of cancer after smoking.”
Of obesitas-paradox
Small bright spot: immunotherapy works better in people with obesity. But how is that possible? “This is called the obesity paradox, because the risk of cancer and survival after diagnosis are worse in obese people, while obesity actually improves the average response of patients to immunotherapy,” explains the American scientist. “There is a lot of data from the diabetes field showing that obesity leads to increased levels of inflammation in the body. We have figured out how we can use these inflammatory responses in a positive way through immunotherapy. The ultimate goal was to strengthen immunity against malignant tumors.”
The different roles of a macrophage
Rathmell continues to talk about the role of macrophages in this. “Macrophages influence all kinds of processes in the human body, both positive and negative. They can promote healing, but also cause harmful inflammation. In macrophages that are active in tumors, the healing side emerges. They see the tumor tissue as a wound and tend to want to repair this damage. In practice, this ensures that the cancer cells receive support. An important goal of ours is to convert those macrophages from the healing type to the type that incites more inflammatory responses. In this way, the tumor becomes weaker and it is possible to ultimately destroy the cancer.”
Team macrofaag
The studydie in Nature has been published, shows that obesity activates the molecule PD-1 of macrophages. As a result, the healing side predominates. “By blocking PD-1, the macrophages can switch to inciting inflammatory responses and thus strengthen the immune response against the tumors. Blocking PD-1 in cancer immunotherapy releases both macrophages and T cells. In this way, an increased anti-tumor response is created,” says Rathmell.
The scientists conducted research in obese and slim mice with cancer and also analyzed tumor samples from people with kidney cancer or endometrial cancer. “Research into cancer immunotherapy has largely focused on T cells, because these are the immune cells that can kill cancer cells,” he said. “But macrophages play an important role in influencing what T cells do. I’ve always been on ‘team macrophage’. Macrophages are like garbage trucks: they clean up the mess. They also have an enormous arsenal of options to strengthen the immune response and they can be controlled and manipulated better than other immune cells,” he concludes.
What is a macrophage?
Macrophages are a type of white blood cells that are part of our immune system. They act as ‘cleaners’ and play a crucial role in identifying, breaking down and removing bacteria, dirt, dead cells and other external substances that enter the body. Macro means big; phage comes from phagocytosis, which means to eat. They eat and break down bacteria, fungi and viruses very effectively. Macrophages can also pass on information to other immune cells.
What are checkpoint inhibitors?
Checkpoint inhibitors or checkpoint inhibitors are a form of immunotherapy against cancer. The immune system has various ‘checks and balances’ that prevent immune cells from overreacting against the body’s own body. Some forms of cancer take advantage of this: they protect themselves against the immune system by stimulating such checkpoints (by expressing PD-1). By treating cancer patients with inhibitors of checkpoint receptors, the brakes are taken off the immune system, so to speak, and the cancer cells will be attacked much more effectively.
PD-1 is a membrane protein found on various immune cells, including cytotoxic T cells. When the PD-1 receptor is bound by PD-1, the cell will no longer take action. In other words, an activated PD-1 receptor silences the immune response.
The combination of checkpoint inhibitors is considered a breakthrough in cancer immunotherapy. Metastatic skin cancer and lung cancer in particular, which until recently were hardly treatable, have a much better prognosis thanks to checkpoint inhibitors.
