期刊
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
卷 23, 期 3, 页码 398-404出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.bbmt.2016.11.018
关键词
NK cell; Adoptive immunotherapy; Cytokines; NK cell education; NK cell memory
资金
- Howard Hughes Medical Institute
- Translational TL1 Program [UL1 TR000448]
- National Institutues of Health/National Cancer Institute [F32 CA200253]
- Siteman Cancer Center Team Science and Siteman Investment Program Awards
- Gabrielle's Angel Foundation for Cancer Research
- Leukemia developmental research grant [SPORE P50 CA171963]
- NCI Cancer Center [P30CA91842]
- The Siteman Cancer Center Flow Cytometry and Immunomonitoring Laboratory Core resources
Cytokine-induced memory-like natural killer (NK) cells differentiate after short-term preactivation with IL-12, IL-15, and IL-18 and display enhanced effector function in response to cytokines or tumor targets for weeks after the initial preactivation. Conventional NK cell function depends on a licensing signal, classically delivered by an inhibitory receptor engaging its cognate MHC class I ligand. How licensing status integrates with cytokine-induced memory-like NK cell responses is unknown. We investigated this interaction using killer cell immunoglobulin-like receptor- and HLA-genotyped primary human NK cells. Memory-like differentiation resulted in enhanced IFN-gamma production triggered by leukemia targets or Fc gamma Rllla ligation within licensed NK cells, which exhibited the highest functionality of the NIC cell subsets interrogated. IFN-gamma production by unlicensed memory-like NK cells was also enhanced to a level comparable with that of licensed control NK cells. Mechanistically, differences in responses to Fc gamma RIIIa-based triggering were not explained by alterations in key signaling intermediates, indicating that the underlying biology of memory-like NK cells is distinct from that of adaptive NK cells in human cytomegalovirus-positive individuals. Additionally, memory-like NK cells responded robustly to cytokine receptor restimulation with no impact of licensing status. These results demonstrate that both licensed and unlicensed memory-like NIC cell populations have enhanced functionality, which may be translated to improve leukemia immunotherapy. (C) 2017 American Society for Blood and Marrow Transplantation.
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