Cytokines drive the formation of memory-like NK cell subsets via epigenetic rewiring and transcriptional regulation
Jennifer A. Foltz, Jennifer Tran, Pamela Wong, Changxu Fan, E. E. Schmidt, Bryan Fisk, Michelle Becker‐Hapak, David A. Russler‐Germain, Jeanette Johnson, Nancy D. Marín, Celia C. Cubitt, Patrick Pence, Joseph Rueve, Sushanth Pureti, Kimberly Hwang, Feng Gao, Alice Y. Zhou, Mark P. Foster, Timothy Schappe, Lynne Marsala, Melissa M. Berrien-Elliott, Amanda F. Cashen, Jeffrey J. Bednarski, Elana J. Fertig, Obi L. Griffith, Malachi Griffith, Ting Wang, Allegra A. Petti, Todd A. Fehniger
Abstract
Activation of natural killer (NK) cells with the cytokines interleukin-12 (IL-12), IL-15, and IL-18 induces their differentiation into memory-like (ML) NK cells; however, the underlying epigenetic and transcriptional mechanisms are unclear. By combining ATAC-seq, CITE-seq, and functional analyses, we discovered that IL-12/15/18 activation results in two main human NK fates: reprogramming into enriched memory-like (eML) NK cells or priming into effector conventional NK (effcNK) cells. eML NK cells had distinct transcriptional and epigenetic profiles and enhanced function, whereas effcNK cells resembled cytokine-primed cNK cells. Two transcriptionally discrete subsets of eML NK cells were also identified, eML-1 and eML-2, primarily arising from CD56 bright or CD56 dim mature NK cell subsets, respectively. Furthermore, these eML subsets were evident weeks after transfer of IL-12/15/18–activated NK cells into patients with cancer. Our findings demonstrate that NK cell activation with IL-12/15/18 results in previously unappreciated diverse cellular fates and identifies new strategies to enhance NK therapies.