A new mechanism for activating the immune system against cancer cells allows immune cells to detect and destroy cancer cells better than before, according to a study published in the journal Nature.
The focus of the study is a mechanism that routinely serves the cell by marking human virus-like genes in order to avoid identifying them as viruses. Now an international team has discovered that when inhibiting this mechanism, the immune system can be harnessed to fight cancer cells in a particularly efficient manner, and most effectively in lung cancer and melanoma.
"We found that if the mechanism is blocked, the immune system is much more sensitive. When the mechanism is deactivated, the immune system becomes much more aggressive against the tumor cells," said the author.
In recent years, a new generation of cancer drugs has been developed which blocks proteins that inhibit immune activity against malignant tumors. These drugs have shown remarkable success in several tumor types. This year's Nobel Prize in Medicine was awarded to James Allison and Tasuku Honjo, who discovered the key genes of this mechanism. Despite this achievement, the current generation of drugs helps only a small number of patients, while most of the drugs fail to cause the immune system to attack the tumor.
Most patients with cancer either do not respond to immune checkpoint blockade or develop resistance to it, often because of acquired mutations that impair antigen presentation.
The authors show that loss of function of the RNA-editing enzyme ADAR1 in tumor cells profoundly sensitizes tumors to immunotherapy and overcomes resistance to checkpoint blockade. In the absence of ADAR1, A-to-I editing of interferon-inducible RNA species is reduced, leading to double-stranded RNA ligand sensing by PKR and MDA5; this results in growth inhibition and tumor inflammation, respectively.
Loss of ADAR1 overcomes resistance to PD-1 checkpoint blockade caused by inactivation of antigen presentation by tumor cells. Thus, effective anti-tumor immunity is constrained by inhibitory checkpoints such as ADAR1 that limit the sensing of innate ligands.
The induction of sufficient inflammation in tumors that are sensitized to interferon can bypass the therapeutic requirement for CD8+ T cell recognition of cancer cells and may provide a general strategy to overcome immunotherapy resistance. It is hoped that the new discovery will allow enhanced activity of the immune system to attack cancer cells. A number of companies have already begun research to screen for drugs that will operate on the basis of this discovery.
Blocking RNA-editing enzyme in tumors to overcome drug resistance
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