Cytokines Drive the Formation of Memory-Like NK Cell Subsets via Epigenetic Rewiring and Transcriptional Regulation

Infectious Diseases Medicine Cell Biology Biochemistry Oncology Life Sciences Immunology
cytokines memory-like NK cells epigenetic rewiring transcriptional regulation immunotherapy

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In the context of today’s rapid advancement in science and technology, immunotherapy with natural killer (NK) cells has attracted widespread attention in the scientific community for their potential advantages in combating tumors and viral infections. Especially, the discovery of memory-like NK cells has brought new hope for NK cells as an anticancer therapy. The molecular mechanisms between NK cell activation and their memory functions are not fully understood, presenting new challenges for researchers.

This study, conducted by Jennifer A. Foltz et al., was published on June 28, 2024, in the journal “Science Immunology” under the title “Cytokines drive the formation of memory-like NK cell subsets via epigenetic rewiring and transcriptional regulation”. The research team is from the Washington University School of Medicine in St. Louis and its affiliated research institutes.

The study explores how activated NK cells, relevant to cancer treatment, differentiate into memory-like (ML) NK cells through epigenetic reprogramming and transcriptional regulation. The study illustrates that through interactions with interleukin-12 (IL-12), IL-15, and IL-18, NK cells can differentiate into enriched memory-like (EML) NK cells or transform into effector conventional NK (EffCNK) cells. These two different fates of NK cells exhibit differences in transcriptional and epigenetic characteristics as well as functions, where EML NK cells show a more pronounced enhancement.

The study details the research process, including specific experimental procedures and scientific conclusions drawn. First, by integrating ATAC-seq (used to determine chromatin accessibility), CITE-seq (combining single-cell transcriptomics and surface protein analysis), and functional analyses, the research team found that NK cells can be reprogrammed to EML NK cells or maintained as EffCNK cells after IL-12/15/18 activation. Importantly, they further identified two transcriptionally distinct subgroups in EML NK cells, namely EML-1 and EML-2, which mainly originate from the CD56bright or CD56dim mature NK cell subgroups.

At the epigenetic level, data analysis revealed changes in chromatin accessibility after NK cell activation, suggesting that the activity of specific genes may be enhanced or reduced. Notably, after IL-12/15/18 activation, the chromatin accessibility of the CNS-1 region (a critical regulatory area) and the promoter region of the IFNG gene significantly increased, which aligns with previous theories. This indicates that when NK cells are activated in a certain way, certain genes exhibit epigenetic markers of memory function.

At the transcriptional level, the CITE-seq method was used to explore the functional and gene expression differences of EML NK cell subgroups from a single-cell perspective. EML-1 and EML-2 cells show significant differences in the expression of specific natural killer cell receptors, cytokines, and transcription factors, suggesting that they may play different immunological roles. Furthermore, analysis of patient callbacks shows that EML NK cells can persist in the body for several weeks, providing a feasible application prospect for NK cell therapy.

The scientific value of this study lies not only in elucidating the formation of memory-like NK cells and their regulatory mechanisms but also in providing new perspectives and strategies for immunotherapy research. The discovery of different EML NK cell subgroups means that NK cell therapies can be customized according to specific medical needs to achieve more precise and effective therapeutic outcomes. Additionally, this study has potential clinical significance for explaining and predicting patient responses to NK cell therapy.

In summary, the focus and highlights of the research are: identifying the existence of EML NK cells and their distinction into two significantly different subgroups, EML-1 and EML-2; elucidating the origins, epigenetic characteristics, and transcriptional features of these two subgroups; revealing their unique roles in NK cell-induced memory functions; and discussing the relevance of these discoveries to the clinical application of NK cells. The study indicates the possibility of stimulating memory-like NK cells, providing a deeper understanding and potential improvements for NK cells as future anticancer treatments.