Nature: reactivating the paralyzed immune system to attack fatal brain cancer

June 02, 2021

Glioma is the most common primary central nervous system tumor. Because it has no obvious boundary with normal brain tissue, it is difficult to completely remove. Therefore, it is not very sensitive to radiotherapy and chemotherapy, and it is easy to relapse. At present, there is no effective response plan. In order to solve this problem, scientists try to find an innovative treatment for glioma by using the immune system through therapeutic vaccine or immunotherapy, so as to benefit cancer patients who have no medicine to treat as soon as possible. Recently, researchers from German Cancer Research Center (DKFZ), medical center of Freiburg University and Mannheim Medical School of Heidelberg University have jointly published an article entitled tryptophan metabolic drives dynamic immunosuppressive myeloid states in IDH constant gliomas in nature cancer, a top academic journal. The study found that glioma cells can be reprogrammed to invade immune cells through a common mutation, thus "paralyzing" the body's immune defense against tumors. To this end, researchers have developed an innovative anti-tumor therapy to reactivate the paralyzed immune system, that is, to combat glioma through therapeutic vaccines or immunotherapy.

https://doi.org/10.1038/s43018-021-00201-z

Interestingly, gliomas are not entirely composed of cancer cells. Up to 50% of gliomas are composed of microglia and monocyte derived macrophages, which are collectively referred to as glioma associated myeloid cells (GAM). However, although macrophages are often referred to as "cell scavengers", they are "powerless" in the face of glioma and are not their rivals at all. To this end, researchers began to look for other breakthroughs to combat glioma. The mutant gene "isocitrate dehydrogenase (IDH)" was detected in 70% of gliomas. Researchers found that the mutation of isocitrate dehydrogenase (IDH) can cause glioma cells to release tumorigenic (R) - 2-hydroxyglutaric acid (r-2-hg), inhibit the immune system and T cell activity, make the invading macrophages reprogrammed, block the immune response of tumor, and cause serious "immune paralysis", It's easy to escape the human immune system.

IDH mutation causes glioma cells to release r-2-hg

But what makes glioma cells so rampant?

To find out, researchers have deciphered the molecular mechanism of r-2-hg reprogramming macrophages. It was found that r-2-hg, a cancer promoting metabolite, interfered with the amino acid metabolism of "cell scavenger" macrophages and activated the central immune system regulatory molecule aryl hydrocarbon receptor (AHR), thus causing macrophages to produce immunosuppressive response.

AHR signal attenuates the function of macrophages in IDH mutant gliomas

Therefore, in view of the negative core role of aromatic hydrocarbon receptors, the researchers decided to terminate the function of this key molecule in order to activate the paralyzed immune system. The researchers combined immune checkpoint blocking T cell activation immunotherapy with small molecule AHR inhibitors in animal models and found that the therapy could effectively prolong the life of IDH mutant tumor mice.

Anti tumor immunity can be reversed by pharmacological inhibition of AHR

"Our current research results show how to avoid the immunosuppressive environment in the brain and further improve the effectiveness of this vaccine," said researchers at the German Cancer Research Center (DKFZ). In the near future, we will further verify in an early clinical trial that the therapeutic vaccine against IDH mutant diffuse glioma can effectively trigger the expected immune response to help more effectively fight this disease which is almost incurable at present. " In the future, it is expected that more patients will benefit from the treatment, completely change the pattern of cancer treatment, and bring them hope for the future.

reference material:

[1] https://www.nature.com/articles/s43018-021-00201-z#Abs1

[2] https://medicalxpress.com/news/2021-05-paralyzed-immune-cells-reactivated-brain.html

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