Spanish researchers discover possible key to enhance immunotherapy cancer treatment: anti-inflammatories such as aspirin

Millions of people owe their lives to Japanese scientist Tasuku Honjo and American James Allison, fathers of immunotherapy, one of the greatest revolutions in the history of medicine. In 1992, Honjo discovered a human protein, PD-1, which acts as a brake on the body’s defenses. By inhibiting it with a drug approved in 2014, white blood cells are released and attack cancer cells with greater ferocity. Some previously incurable tumors are no longer a death sentence, but the enemy is still powerful. More than half of cases of melanoma with metastasis, for example, are resistant to the drug. Two Spanish scientists — Anais Elewaut, 29, from Málaga, and Guillem Estivill, 28, from Barcelona — have now discovered, through experiments on rodents, a promising way to enhance the miraculous immunotherapy: some anti-inflammatories, such as aspirin.

“We see that mice [genetically modified to develop tumors similar to those in humans] that receive immunotherapy and anti-inflammatories live much longer, in general. We even have mice that are 100% cured. Without the anti-inflammatory, they are resistant to immunotherapy,” Estivill explains by phone. The two Spanish scientists work at the Research Institute of Molecular Pathology in Vienna (Austria), under the orders of biologist Anna Obenauf. Their study was published Wednesday in the journal Nature, a benchmark for the best science in the world.

The human body’s defenses, white blood cells, are formed inside the bones, but some types travel to the thymus — a small gland in the chest — to mature and become cytotoxic T lymphocytes, capable of destroying cells infected by viruses or bacteria. Cancer, formed when human cells themselves multiply in an uncontrolled manner, is characterized by its ability to evade the immune system, which often does not recognize it as a threat.

The Vienna team has identified a crucial player in the activation of these killer T cells that had so far gone unnoticed: monocytes, another type of white blood cell formed in bone marrow. The new work shows that monocytes travel through the blood and can capture fragments of cancer cells, displaying them to T cells, which then reactivate and attack the tumor.

The study also sheds light on cancer’s strategy for hiding from defenses. Tumor cells increase the production of prostaglandin E2, a lipid substance that blocks the action of monocytes. At the same time, they decrease the production of interferons, proteins that stimulate the immune system. The Vienna group argues that anti-inflammatory drugs that inhibit cyclooxygenase, such as aspirin, are “a promising strategy” to increase the effectiveness of immunotherapy, since they block the production of inflammatory molecules, such as prostaglandin E2.

Estivill is optimistic, given the previous results observed in humans. “We have done a meta-analysis and we have seen that, in clinical trials of immunotherapy, patients who have reported taking anti-inflammatory drugs have a better response, not only aspirin, but any cyclooxygenase inhibitors, such as ibuprofen and many others that they take regularly to mitigate pain,” he says.

The Barcelona biologist points out that these anti-inflammatories provide short-term benefits for cancer patients by slowing the progression of the disease, but over time the tumor reappears. In their study, the Vienna group proposes different combinations of immunotherapy, anti-inflammatories at appropriate doses, and other types of drugs that induce the production of interferons. “It works in mice. We have demonstrated this in melanoma and in pancreatic, lung, and colon cancer,” stresses Estivill, who recognises that human tumors are “much more heterogeneous,” so it remains to be seen whether the strategy works in the same way in people.

Elewaut, a biotechnologist whose parents are Belgian, explains that the levels of prostaglandin E2 in tumors are very high. “I think that, to inhibit this process and for immunotherapy to work better, you are going to need a lot of aspirin and a lot of ibuprofen, and the problem is that these drugs also have many side effects: stomach problems, cardiovascular problems, etc. So we have to try to combine aspirin, immunotherapy, and probably other drugs,” she says. “People should not think that aspirin alone will cure cancer.”

The head of the Austrian laboratory, Anna Obenauf, confirms that “aspirin is one of several possibilities,” but there are similar, more potent and specific drugs, such as celecoxib, used to relieve pain and inflammation in arthritis. “Clinical trials are already underway with several of these drugs. I suspect that they will show some effect, but in our study we demonstrate how to enhance that effect with additional combination therapies,” she says. Obenauf trained more than a decade ago in the laboratory of the Spanish pharmacologist Joan Massagué, director of the Sloan Kettering Institute, a center dedicated to cancer research in New York.

Biologist Marisol Soengas, president of the Spanish Association for Cancer Research, applauds the new work, in which she did not participate. “The study is very rigorous and very complete, because it uses very diverse cellular models and also different models of genetically modified animals,” she explains. Soengas is also the head of the Melanoma Group at the National Cancer Research Centre in Madrid. In her opinion, all caution must still be maintained, while waiting to see the results of the combination of anti-inflammatories with the most common immunotherapies, such as the so-called immune checkpoint inhibitors.

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