Sustained effector function of IL-12/15/18–preactivated NK cells against established tumors

Abstract

NK cells treated with a cocktail of IL-12, IL-15, and IL-18 persist with sustained effector function in vivo and enhance tumor immunotherapy.

Natural killer cell memory in infection, inflammation and cancer

“…Of note, humans with genetic defects in IL-12 production were not reported to have impaired resistance to HCMV 52 , indicating the existence of redundant pathways for HCMV immunity. IL-12 and IL-18 produced during MCMV infection lead to upregu lation of CD25, the IL-2Rα chain forming the high-affinity IL-2 receptor, in NK cells 53,54 . Expression of CD25 enables NK cells to respond to low amounts of IL-2 (REF.…”

“…This long-term competence for IFNγ production was cell intrinsic and maintained after homeostatic proliferation 21 . Human NK cells that are briefly exposed to IL-12, IL-15 and IL-18, washed and then cultured in IL-2 or IL-15 for additional days also produce highly elevated amounts of IFNγ upon restimulation with tumour cell lines or with IL-12 and IL-15 (REFS 23,54). Similar to observations with human HCMV-driven CD94-NKG2C + NK cells, the brief exposure of human NK cells to IL-12, IL-15 and IL-18 resulted in stable demethylation of the IFNG conserved non-coding sequence 1 (CNS1) 62 .…”

“…Whether these cytokines also have a physio logical role in the generation of memory NK cells during viral infection in the absence of a cognate interaction between the NK cells and pathogens in other models needs to be determined. Of note, cytokineinduced memory cells could be of high therapeutic value as illustrated by the observation that antitumour immune responses were greatly improved upon adoptive transfer of cytokine-induced memory NK cells into tumour-bearing mice 54 .…”

Sweet Is the Memory of Past Troubles: NK Cells Remember

“…While this phenomenon could be deleterious to the host in some situations, the ability to generate in vitro NK cells with enhanced function presents an exciting new avenue for NK cell-based immunotherapies. Using mouse NK cells activated with IL-12, IL-15, and IL-18, Cerwenka and colleagues found that these adoptively transferred memory-like NK cells had enhanced efficacy against established tumors when combined with radiation therapy in a mouse model (Ni et al 2012). This effect was due to their cooperation with CD4 + T cells, which provided the source of IL-2 that drove the rapid proliferation of these NK cells.…”

“…Ni et al (2012) and Romee et al (2012) have developed in vitro culture methods for NK cells, similar to those used in mouse studies. By briefly activating purified human NK cells with IL-12, IL-15, and IL-18 and then resting them for an extended period in the absence of cytokines, these groups generated NK cells with a distinct phenotype and enhanced function.…”