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The SIRPα-CD47 immune checkpoint in NK cells.

  • Author(s): Deuse, Tobias;
  • Hu, Xiaomeng;
  • Agbor-Enoh, Sean;
  • Jang, Moon K;
  • Alawi, Malik;
  • Saygi, Ceren;
  • Gravina, Alessia;
  • Tediashvili, Grigol;
  • Nguyen, Vinh Q;
  • Liu, Yuan;
  • Valantine, Hannah;
  • Lanier, Lewis L;
  • Schrepfer, Sonja
  • et al.
Abstract

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

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