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The SIRPa-CD47 immune checkpoint in NK cells. The Journal of experimental medicine Deuse, T. n., Hu, X. n., Agbor-Enoh, S. n., Jang, M. K., Alawi, M. n., Saygi, C. n., Gravina, A. n., Tediashvili, G. n., Nguyen, V. Q., Liu, Y. n., Valantine, H. n., Lanier, L. L., Schrepfer, S. n. 2021; 218 (3)

Abstract

Here we report on the existence and functionality of the immune checkpoint signal regulatory protein a (SIRPa) in NK cells and describe how it can be modulated for cell therapy. NK cell SIRPa 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 SIRPa+ primary NK cells, but not against SIRPa- NKL or NK92 cells. SIRPa 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 SIRPa-CD47 axis was found to be highly species specific. Together, the results demonstrate that disruption of the SIRPa-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.

View details for DOI 10.1084/jem.20200839

View details for PubMedID 33416832