A Role for m6A Methylation in the Immune Response of Natural Killer Cells Toward Cancer

The body’s first line of defense against infection is the innate immune system. Although it is non-specific and less effective than the acquired immune system, it responds to invading pathogens much faster, holding off an immunological threat until a specific response can be mobilized.

One integral part of the innate immune system is natural killer cells (NK). As their name suggests, these cells are capable of killing affected cells autonomously while also signaling an immune response as they secrete pro-inflammatory cytokines to essentially liquefy their targets.

NK cells attack quickly and can recognize various infected cells from viruses, parasites, and bacteria. They can also selectively target and kill malignant cells, triggering powerful antitumor activities. Although tumors eventually learn to resist NK cells, scientists are interested in engineering them to endure and overcome cancer progression. One new area of research that has been increasingly studied in cancer and could provide some answers is epigenetics.

Epigenetic studies look into how genes function within a cell – which ones are turned “on” or “off” and what control they have on cellular activity. Epigenetic modifications do not alter the DNA sequence but regulate the production of proteins, ensuring that a cell operates properly. Environmental stimuli, like a person’s diet or chemical compounds, can influence the epigenome and upset cellular processes. Certain diseases like cancer have been found to contain errors in epigenetic factors that allow tumors to grow and the immune system to fail.   

In NK cells, the effector functions require certain proteins for activation. However, little is known about how these molecules regulate NK cells. Past research strongly suggests that epigenetic factors regulate the processes of NK cells, including chromatin remodeling, DNA methylation, histone modifications, and RNA modifications.

To better understand NK cells’ role in tumor immune surveillance, scientists from The University of Science and Technology of China (USTC) decided to investigate m6A RNA methylation. Their results revealed that this particular epigenetic modification is involved in preserving the stability and antitumor immune function of NK cells – making m6A RNA modification a promising route of study for developing NK cell-based cancer therapies.

RNA modification has gained increasing interest in recent years with the discovery of N6-methyladenosine (m6A), a predominant mRNA and DNA modification in most eukaryote cells. It has been shown to affect multiple aspects of RNA metabolism, including RNA processing and translation, nuclear export, and decay.

The m6A RNA modification, like other epigenetic mechanisms, is dynamic and reversible, and it is recognized at specific regions of the transcript by components known as “writers”, “erasers”, and “readers”. Writer proteins get interpreted by reader proteins, which can be removed by the activities of eraser enzymes.

In the USTC study, the researchers first analyzed microarray data of tumor-infiltrating and neighboring NK cells from patients with liver cancer and normal liver tissue. They found that m6A “writers” methyltransferase-like 3 (METTL3) mRNA levels were 75% lower in tumor-infiltrating NK cells of the liver cancer patients than healthy controls.  

Mice models for cancer confirmed the positive correlation in amount and effector functions of NK cells. Reduced METTL3 protein expression resulted in lower quantifiable levels of m6A and fewer and weaker NK cells. As well, depletion of METTL3 proved to alter the homeostasis of NK cells. Mice deprived of this m6A “writer” had accelerated tumor growth, widespread metastases, and a lower survival rate.

Upon further analysis with MeRIP-Seq and METTL3-RIP-seq analysis, the team also discovered that METTL3-mediated m6A methylation enables an immune response by activating the AKT-mTOR and MAPK-ERK signaling pathways, potentially through increasing SHP-2 expression. However, the precise mechanisms involved in this process are not known.

Overall, the findings from this study describe the importance of METTL3-mediated m6A methylation for facilitating homeostasis and protection against tumorigenesis in NK cells. It’s hoped that the insights provided here will lead to future epigenetic research into NK cell-based or METTL3-related therapeutic strategies for various types of cancer.

Source: Song H et al. (2021).METTL3-mediated m6A RNA methylation promotes the anti-tumor immunity of natural killer cells. Nature Communications.