Barkal et al. showed that CD24, a GPI-linked protein overexpressed on ovarian, TNBC, and other solid tumors, inhibited phagocytosis through interaction with Siglec-10 on tumor-associated macrophages. Siglec-10+ macrophages cultured with MCF-7 breast cancer cells and anti-CD24 exhibited potentiated phagocytosis that was synergistic with anti-CD47. In patients, low CD24 levels correlated with increased relapse-free and OS in ovarian and breast cancer. In mice, treatment of MCF-7 tumors with anti-CD24 significantly decreased tumor burden, suggesting the potential of CD24 blockade for immunotherapy.
Contributed by Katherine Turner
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 CD47(1), 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 cancers(4,5). 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.
Author Info: (1) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Ludwig Center for Cancer Stem Cell Research and Medicine,
Author Info: (1) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Stanford Medical Scientist Training Program, Stanford University, Stanford, CA, USA. (2) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (3) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (4) Department of Physics, Stanford University, Stanford, CA, USA. (5) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (6) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (7) Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Stanford University School of Medicine, Stanford, CA, USA. (8) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Department of Urology, Stanford University School of Medicine, Stanford, CA, USA. (9) Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Stanford University School of Medicine, Stanford, CA, USA. (10) Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. (11) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. irv@stanford.edu. Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA. irv@stanford.edu. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. irv@stanford.edu. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. irv@stanford.edu.
