The Sirp Alpha-Cd47 Immune Checkpoint In Nk Cells

Here we report on the existence and functionality of the immune checkpoint signal regulatory protein alpha (SIRPa alpha) in NK cells and describe how it can be modulated for cell therapy. NK cell SIRP alpha is up-regulated upon IL-2 stimulation, interacts with target cell CD47 in a threshold-dependent manner, and counters other stimulatory signals, including IL-2, CD16, or NKG2D. Elevated expression of CD47 protected K562 tumor cells and mouse and human MHC class I-deficient target cells against SIRP alpha(+) primary NK cells, but not against SIRP alpha(-) NKL or NK92 cells. SIRP alpha deficiency or antibody blockade increased the killing capacity of NK cells. Overexpression of rhesus monkey CD47 in human MHC-deficient cells prevented cytotoxicity by rhesus NK cells in a xenogeneic setting. The SIRP alpha-CD47 axis was found to be highly species specific. Together, the results demonstrate that disruption of the SIRP alpha-CD47 immune checkpoint may augment NK cell antitumor responses and that elevated expression of CD47 may prevent NK cell-mediated killing of allogeneic and xenogeneic tissues.