Several blood pressure medications may improve the effectiveness of cancer immunotherapy

n Credit: Pixabay/CC0 Public Domain

According to a study from Ludwig Cancer Research, several chemicals that were once used to treat hypertension may also aid the immune system’s ability to more effectively attack cancer cells. These discoveries, which were published in the most recent edition of Nature, may eventually be used to greatly increase the efficacy and application of cancer immunotherapy.n

Only 30% to 40% of tumors may now be successfully treated with immunotherapy, according to Beno?t Van den Eynde, professor of tumor immunology at the University of Oxford, co-director of the de Duve Institute, and member of the Ludwig Institute for Cancer Research. Many tumors are resistant, primarily as a result of their T cells not being sufficiently reactive. We learned that medications once used to treat hypertension may have a very intriguing impact in preventing these forms of immunotherapy-resistant cancers.?

The immune system protects against disease by destroying foreign substances and pathogens, such as bacteria and viruses. T lymphocytes, a type of white blood cell, are active components in this process. They recognize and destroy cells that appear foreign.n

Cancer cells, however, are not foreign and are therefore often not recognized and attacked by T lymphocytes. But about thirty years ago, Thierry Boon and his colleagues at the former Brussels Branch of the Ludwig Institute for Cancer Research at the de Duve Institute discovered specific markers on the surface of tumor antigens?that can be recognized by T cells that then destroy the cancerous cells.n

This work paved the way for cancer immunotherapy, a treatment approach that helps T cells destroy cancerous cells. Thanks to T cells’ specificity and memory of tumor antigens, immunotherapy makes it possible to treat advanced cancers with some success. It is now used worldwide. However, such therapies are not equally effective in all patients or against all types of cancer.n

In the current study, a team led by Jingjing Zhu in Van den Eynde’s laboratory shows that anti-hypertensive drug-molecules known as a2-adrenergic receptor (a2AR) agonists also influence the behavior of macrophages?white blood cells that engulf and digest debris from pathogens, such as cancer cells, microbes and foreign substances. While doing that job, macrophages also alert T cells of any abnormalities they encounter, presenting suspicious antigens to the cells to trigger a possible immune response.n

Zhu, Van den Eynde and colleagues discovered that alongside their known hypotensive and anesthetic effects, a2AR agonists can also stimulate macrophages in their role as sentinels, making T cells more reactive and more effective at rejecting cancer cells. The effect extended, most notably, to cancer models that are resistant to standard immunotherapy. This suggests that the new approach could boost the efficacy of clinical immunotherapy, even for the many types of cancer that are largely unresponsive to such interventions.n

These findings also present a rationale for the development of new molecules that might be used in combination with immunotherapy to improve its efficacy.n

“One could imagine using existing blood pressure-lowering drugs,” said Van den Eynde. “But that would be quite risky, owing to the undesired effects and the toxicity of these drugs at the necessary doses. Another approach would be to develop new molecules that would act in the same way on macrophages but would not have the unwanted toxic effects. We have already made significant progress in this direction.”

More information:
n Jingjing Zhu et al, Tumour immune rejection triggered by activation of a2-adrenergic receptors, Nature (2023). DOI: 10.1038/s41586-023-06110-8

n Provided byn Ludwig Cancer Research
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