Nanoscale restructuring of the immune synapse with an engager enhances NK cell function
Abstract
Engagers are antibody-based therapies which bind immune cell receptors and a target cell ligand. Next-gen engagers typically bind two activating receptors, but the effect of this on immune synapse formation and signaling is unknown. Here, we coligated activating receptors CD16a and NKG2D on natural killer (NK) cells with a CD33-binding anti-acute myeloid leukemia (AML) engager. Superresolution microscopy revealed that coligating CD16a and NKG2D with a single molecule triggered their nanoscale coclustering. This enhanced phosphorylation of CD3ζ, ZAP70, and SLP-76 which augmented secretion of IFN-γ and TNF-α, by NK cells from healthy donors and AML patients. Thus, in addition to connecting immune cells to target cells, the clinical promise of engagers results from their ability to manipulate the nanoscale architecture of the immune synapse.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (8)
Khodor S. Hazime
Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, South Kensington
Sam Sheppard
Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, South Kensington
Olatz Niembro-Vivanco
Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, South Kensington
Cathal Hosty
Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, South Kensington
Heather Thomas
Immuno-Oncology Cellular Therapy Thematic Research Center, Bristol Myers Squibb
Christopher Loosbroock
Immuno-Oncology Cellular Therapy Thematic Research Center, Bristol Myers Squibb
Leanne Peiser
Immuno-Oncology Cellular Therapy Thematic Research Center, Bristol Myers Squibb
Daniel M. Davis
Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, South Kensington