CD24 Is a “Don't Eat Me” Signal That Promotes Tumor Immune Escape

The cell-surface protein CD24 suppresses inflammatory responses and is expressed by several solid tumors, but whether it modulates the immune response to tumors is not known. Barkal and colleagues found that CD24 expression was greatly elevated in triple-negative breast cancer (TNBC) and ovarian cancer; patients with breast cancers who had lower CD24 expression in their bulk tumors had greater overall survival, and patients with ovarian cancer with lower CD24 expression in their bulk tumors had improved relapse-free survival. Samples from primary TNBC tumors had high CD24 expression compared to other cell clusters; further, CD24 levels were elevated in breast and ovarian cancer cells from primary tumors. Additionally, tumor-associated macrophages from breast and ovarian cancers expressed Siglec-10, an inhibitory receptor known to interact with CD24. Co-culture of breast cancer cells with M2-like macrophages expressing Siglec-10 showed that CD24 deletion was sufficient to trigger phagocytosis. Additionally, Siglec-10 blockade with monoclonal antibodies (mAb) increased phagocytosis, as did SIGLEC10 knockout in donor-derived macrophages. Live-cell imaging revealed that treating breast cancer cells with a mAb against CD24 made them more vulnerable to engulfment into the low pH phagolysosome, and FACS analyses showed an increase in phagocytosis after treatment with a mAb against CD24. Deletion of SIGLEC10 decreased the response to CD24 blockade. CD24 expression was correlated not only with response to CD24 blockade, but also with baseline phagocytosis levels, implying a significant role for CD24 as a “don't eat me” signal. Ovarian cancer cells from patients with metastatic ovarian cancer treated with a mAb against CD24 exhibited greater phagocytosis by M2-like macrophages than those treated with a mAb against the known “don't eat me” signal CD47, and cotreatment with both mAbs resulted in an even further increase in phagocytosis. In a mouse breast cancer model, tumors lacking CD24 grew significantly less than wild-type tumors, resulting in a survival advantage, and mice with tumors with wild-type CD24 exhibited reduced tumor growth with anti-CD24 therapy. Collectively, these results suggest that CD24 may be a useful target for immunotherapy, especially for breast and ovarian cancers.

Barkal AA, Brewer RE, Markovic M, Kowarsky M, Barkal SA, Zaro BW, et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature 2019 Jul 31 [Epub ahead of print].

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