Inhibiting autophagy to enhance immune recognition of azacitidine-treated leukemia
Grégory Ehx's laboratory and his Canadian colleagues published an article in the journal Leukemia describing how azacitidine, a drug used against leukemia, works. The mechanism discovered suggests that this drug must be combined with autophagy inhibitors to unleash its full potential.
Acute myeloid leukemia is the most frequent and aggressive form of leukemia in adults. Although this disease responds well to current chemotherapies, most patients are either too old to receive high doses of chemotherapy or eventually relapse and need to be treated with other drugs. Azacitidine (AZA) is the main alternative to chemotherapy and is the first-line treatment for elderly patients. However, relapse is also common after this therapy. It is therefore important to understand in detail how it works to improve its effectiveness, for example by combining it with other drugs. This is why Grégory Ehx (Hematology Laboratory - GIGA Institute) and his colleagues at the University of Montreal, Claude Perreault and Pierre Thibault, set out to better understand how AZA works.
AZA is what is called a hypomethylating agent; it restores the expression of inhibited genes in cancer cells. This inhibition typically occurs through gene methylation in DNA. AZA thus acts as an inducer of gene expression. In cancer, some genes responsible for controlling cell proliferation are methylated, allowing cells to proliferate more rapidly and in an uncontrolled manner. In general, it is considered that treating with AZA restores the expression of these genes and thus regulates the proliferation of cancer cells.
However, G. Ehx and his team discovered that AZA also induces the expression of endogenous retroelements (ERE), ancient viruses hidden in our DNA and considered dormant because their genomic region is heavily methylated. These EREs are very interesting because they are non-functional (unable to generate viral particles and spread throughout the body) but remain capable of being expressed and generating potentially deleterious inflammatory responses. In fact, the researchers found that the expression of these EREs led to antiviral inflammatory reactions and disruption of proliferative processes in leukemia cells from patients. EREs therefore directly contribute to the anti-leukemic effects of AZA.
Mechanisms of action of AZA. On one hand, it inhibits DNA methylation and induces EREs, and on the other hand, it inhibits protein translation, inducing the formation of protein aggregates. The EREs then generate double-stranded RNAs that are recognized by the cell's antiviral defense systems, such as the MDA5 helicase. This type of defense can lead to a slowdown in cell proliferation or cell death. Meanwhile, the aggregates induce autophagy, which degrades the double-stranded RNAs of the EREs, preventing them from being translated into MHC peptides and reducing their ability to induce antiviral defenses.
Going further, researchers then tried to demonstrate that these ancient viruses contribute to the immune recognition of leukemic cells via the generation of MHC-I peptides on the cell surface. These peptides generally derive from proteins expressed by healthy cells and are ignored by cytotoxic T cells. However, if a foreign protein (such as one from a virus that has infected the cell) generates such a peptide, it will be recognized by cytotoxic T cells, which will eliminate the infected cell. Since EREs are ancient viruses, it was logical to think that their expression could contribute to the elimination of leukemic cells via MHC-I peptide presentation.
To the researchers' surprise, no MHC-I peptides deriving from EREs were induced by AZA. They then tried to discover why and realized that AZA induces a recycling process called autophagy in leukemia, mainly due to the inhibition of protein translation mediated by AZA. This autophagy, in turn, was involved in the degradation of EREs, preventing them from being translated into MHC peptides. Indeed, inhibiting autophagy at the same time as treating with AZA further increased antiviral responses and restored the generation of peptides, making leukemic cells recognizable by the immune system. Ultimately, the researchers found that patients with leukemia expressing many EREs but little autophagy showed more T lymphocyte responses than those expressing many EREs but also a lot of autophagy.
This work thus opens up exciting new therapeutic avenues for acute myeloid leukemia since many autophagy inhibitors already exist in the clinic, such as the famous chloroquine. G. Ehx's team will now attempt to understand if these EREs can play a role in the response to other treatments and try to specifically target their MHC-I peptides with innovative immunotherapies.
Reference
Autophagy degrades immunogenic endogenous retroelements induced by 5-azacytidine in acute myeloid leukemia.
Noronha N, Durette C, Cahuzac M, E Silva B, Courtois J, Humeau J, Sauvat A, Hardy MP, Vincent K, Laverdure JP, Lanoix J, Baron F, Thibault P, Perreault C, Ehx G.
Leukemia, 2024
