Over the past fifteen years, there has been rapid development in the field of immunotherapy. While traditional cancer treatment attacks cancer cells with radiation, surgery, and chemotherapy, immunotherapy uses a different approach.
"With immunotherapy, the focus is not directly on the cancer cells themselves, but on the immune system within the microenvironment surrounding the tumor. The tumor actually contains not only cancer cells but also a variety of normal cells from the host, such as fibroblasts and immune cells," explains Professor Fahri Saatcioglu from the Department of Biosciences at the University of Oslo.
"Every day, small tumors form in the body that the immune system recognizes and removes. But in addition to the part that kills unwanted cells, as well as bacteria and viruses, the system also has a part that acts as a brake, stopping it in time so it doesn’t start attacking healthy cells. This brake is called a checkpoint."
Cold cancer types
The trick that cancer cells use is to override the normal regulation of the immune system, keeping the brake on at all times. This way, the immune system senses no danger and allows the cancer cells to grow and spread. However, in certain types of immunotherapy, drugs are used to override these checkpoints, preventing them from stopping the immune cells so that they are free to attack the cancer cells. These drugs are called checkpoint inhibitors, which have revolutionized immunotherapy in the last 15 years.
"There are, however, some types of cancer on which immunotherapy does not work. But for the 20–40 percent of cases where it does, the expected lifespan can increase from just a few months to at least 10–15 years," says Saatcioglu.
The types of cancer that immunotherapy does not work on are called "cold" cancers and include pancreatic cancer, ovarian cancer, breast cancer, and the type that Saatcioglu primarily researches: prostate cancer.
Present in all cells of the body
Prostate cancer is the most common form of cancer among men in Norway, with approximately 5,000 new cases discovered each year. Despite continuous improvement in treatment methods, about one-fifth of patients still die of prostate cancer. New treatment methods are therefore highly welcome.
Titan previously reported that Saatcioglu lab discovered a potential treatment for prostate cancer by blocking a signaling pathway known as IRE1 with the small molecule MKC8866. IRE1 signaling is crucial for cells to manage internal and external stress, and by blocking IRE1, cancer cells lose much of this capability.
“But IRE1 is not unique to cancer cells; it exists in all cells in the body. So, what happens to the other cells in a prostate tumor when we use the MKC8866 molecule to block IRE1? Or when we eliminate it using the gene-editing method CRISPR-Cas9?”
“With the help of a new method called single-cell RNA sequencing, we’ve been able to study what happens to all the cells in the tumor microenvironment,” explains Saatcioglu.
More immune cells attacking the tumor
“When we blocked the IRE1 signaling, we found that the immunosuppressive effects in the tumor microenvironment were significantly reduced. This led us to hypothesize that this might have a beneficial effect on immunotherapy for prostate cancer, something that no one has succeeded in achieving before, except in very special cases, despite several attempts in various large clinical studies."
In other words, blocking IRE1 could potentially turn a cold tumor into a hot one, making it receptive to checkpoint immunotherapy.
“When we targeted prostate cancer with a checkpoint inhibitor alone, we saw only a small effect. Just blocking IRE1 at a low dose caused a slight reduction in tumor growth, but not much,” says Saatcioglu.
"But the combination of a checkpoint inhibitor and IRE1 blockade led to a dramatic reduction in tumor growth in several mouse models. At the same time, the composition of immune cells in the microenvironment in the tumors changed to include more immune cells that attack the cancer cells."
Findings relevant for other cancer types
“We have tested and observed the same effect in four different mouse models, so we are very confident in our conclusions. This is also reflected by the fact that our findings have been published in the prestigious journal Nature Communications.”
The next step is clinical trials, provided they succeed in securing the necessary funding. Saatcioglu primarily researches prostate cancer, but it is natural to ask whether the same treatment could also be applied to other cancer types classified as cold.
“There are recent studies that suggest this. The IRE1 signaling pathway is, as mentioned, present in all cells, which of course includes other types of cancer cells. There is evidence that our findings are also relevant for other types of cancer.”
Scientific article
Unal, Saatcioglu et al.: Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer. Nature Communications, Oct 2024
