The SIRPα-CD47 immune checkpoint in NK cells

Tobias Deuse; Xiaomeng Hu; Sean Agbor-Enoh; Moon K Jang; Malik Alawi; Ceren Saygi; Alessia Gravina; Grigol Tediashvili; Vinh Q Nguyen; Yuan Liu; Hannah Valantine; Lewis L Lanier; Sonja Schrepfer

doi:10.1084/jem.20200839

The SIRPα-CD47 immune checkpoint in NK cells

J Exp Med. 2021 Mar 1;218(3):e20200839. doi: 10.1084/jem.20200839.

Authors

Tobias Deuse^#¹, Xiaomeng Hu^#^{1

2}, Sean Agbor-Enoh^{3

4}, Moon K Jang⁴, Malik Alawi⁵, Ceren Saygi⁵, Alessia Gravina¹, Grigol Tediashvili¹, Vinh Q Nguyen⁶, Yuan Liu⁷, Hannah Valantine^{8

9}, Lewis L Lanier^#¹⁰, Sonja Schrepfer^#^{1

2}

Affiliations

¹ Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology Lab, University of California, San Francisco, San Francisco, CA.
² Sana Biotechnology, Inc., South San Francisco, CA.
³ Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD.
⁴ Laboratory of Applied Precision Omics, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD.
⁵ Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁶ Department of Surgery, University of California, San Francisco, San Francisco, CA.
⁷ Department of Biology, Georgia State University, Atlanta, GA.
⁸ Division of Cardiovascular Medicine, Stanford University, Stanford, CA.
⁹ Laboratory of Transplant Genomics, National Heart, Lung, and Blood Institute, Bethesda, MD.
¹⁰ Department of Microbiology and Immunology, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD47 Antigen / metabolism*
Cells, Cultured
Cytokines / pharmacology
Cytotoxicity, Immunologic / drug effects
Endothelial Cells / drug effects
Endothelial Cells / metabolism
Histocompatibility Antigens Class I / metabolism
Humans
Immune Checkpoint Inhibitors
Killer Cells, Natural / drug effects
Killer Cells, Natural / metabolism*
Macaca mulatta
Macrophages / drug effects
Macrophages / metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Protein Binding / drug effects
Receptors, Immunologic / metabolism*
Species Specificity

Substances

CD47 Antigen
Cytokines
Histocompatibility Antigens Class I
Immune Checkpoint Inhibitors
Ptpns1 protein, mouse
Receptors, Immunologic

Abstract

Publication types

MeSH terms

Substances

Grants and funding