Researchers in the Department of Medicine reveal new ways that human natural killer (NK) cells are rewired by signals through cytokine receptors to generate a memory-like program.
In a report published in Science Immunology, co-first authors Jennifer Foltz, PhD, and Jennifer Tran build on prior work from senior author Todd Fehniger, MD, PhD, WashU Division of Oncology, that identified human memory-like (ML) NK cell immunobiology and translated ML NK cells into the clinic. This study investigated the mechanisms of how the cytokines interleukin (IL)-12, 15, and 18 cooperatively activate and initiate a memory-like program in human NK cells. They identified a subset of enriched memory-like (eML) NK cells that have single cell transcriptional and epigenetic profiles that distinguish them from conventional and adaptive NK cells.
Further, eML were comprised of two subsets (eML-1 and eML-2) with different transcriptional profiles, transcription factor expression, and functional responses to cancer target cells. These subsets had distinct conventional NK cell origins: eML-1 were primarily derived from CD56bright NK cells, while eML-2 differentiated from CD56dim NK cells. Importantly, both eML-1 and eML-2 subsets were detected weeks after transfer of IL-12/15/18-activated NK cells into patients with leukemia participating in ML NK cellular therapy clinical trials at Washington University. This study reveals molecular mechanisms orchestrating the memory-like program, and guides future strategies applying ML NK cells as a cancer immunotherapy.
“This work identifies previously unappreciated heterogeneity in the fates of conventional NK cells stimulated with pro-inflammatory cytokines, with only some differentiating into memory-like NK cells”, says Dr. Fehniger. “The unique epigenetic and single cell programs discovered in this study will serve as a road map to generate genuine memory-like NK cells, and hopefully improve on current approaches to create ML NK cellular therapies.”
