The SIRPα-CD47 immune checkpoint in NK cells.

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

PubMed

Johns hopkins university school of medicine; STANFORD UNIVERSITY; Johns Hopkins University School of Medicine; The Johns Hopkins University School of Medicine; University of California; Pulmonary and Critical Care Medicine; Johns Hopkins University School of Medicine; Stanford University.; Georgia state university; university of california; johns hopkins university school of medicine; Johns Hopkins University,School of Medicine

摘要

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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