CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy

Amira A. Barkal, Rachel E. Brewer, Maxim Markovic, Mark Kowarsky, Sammy A. Barkal, Balyn W. Zaro, Venkatesh Krishnan, Jason Hatakeyama, Oliver Dorigo, Layla J. Barkal and Irving L. Weissman ()
Additional contact information
Amira A. Barkal: Stanford University School of Medicine
Rachel E. Brewer: Stanford University School of Medicine
Maxim Markovic: Stanford University School of Medicine
Mark Kowarsky: Stanford University
Sammy A. Barkal: Stanford University School of Medicine
Balyn W. Zaro: Stanford University School of Medicine
Venkatesh Krishnan: Stanford University School of Medicine
Jason Hatakeyama: Stanford University School of Medicine
Oliver Dorigo: Stanford University School of Medicine
Layla J. Barkal: Stanford University School of Medicine
Irving L. Weissman: Stanford University School of Medicine

Nature, 2019, vol. 572, issue 7769, 392-396

Abstract: Abstract Ovarian cancer and triple-negative breast cancer are among the most lethal diseases affecting women, with few targeted therapies and high rates of metastasis. Cancer cells are capable of evading clearance by macrophages through the overexpression of anti-phagocytic surface proteins called ‘don’t eat me’ signals—including CD471, programmed cell death ligand 1 (PD-L1)2 and the beta-2 microglobulin subunit of the major histocompatibility class I complex (B2M)3. Monoclonal antibodies that antagonize the interaction of ‘don’t eat me’ signals with their macrophage-expressed receptors have demonstrated therapeutic potential in several cancers4,5. However, variability in the magnitude and durability of the response to these agents has suggested the presence of additional, as yet unknown ‘don’t eat me’ signals. Here we show that CD24 can be the dominant innate immune checkpoint in ovarian cancer and breast cancer, and is a promising target for cancer immunotherapy. We demonstrate a role for tumour-expressed CD24 in promoting immune evasion through its interaction with the inhibitory receptor sialic-acid-binding Ig-like lectin 10 (Siglec-10), which is expressed by tumour-associated macrophages. We find that many tumours overexpress CD24 and that tumour-associated macrophages express high levels of Siglec-10. Genetic ablation of either CD24 or Siglec-10, as well as blockade of the CD24–Siglec-10 interaction using monoclonal antibodies, robustly augment the phagocytosis of all CD24-expressing human tumours that we tested. Genetic ablation and therapeutic blockade of CD24 resulted in a macrophage-dependent reduction of tumour growth in vivo and an increase in survival time. These data reveal CD24 as a highly expressed, anti-phagocytic signal in several cancers and demonstrate the therapeutic potential for CD24 blockade in cancer immunotherapy.

Date: 2019
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DOI: 10.1038/s41586-019-1456-0

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