Targeting CD47 in anaplastic thyroid carcinoma enhances tumor phagocytosis by macrophages and is a promising therapeutic strategy

Christian M Schürch, Matthias A Roelli, Stefan Forster, Marie-Hélène Wasmer, Frido Brühl, Renaud Maire, Sergio Di Pancrazio, Marc-David Ruepp, Roland Giger, Aurel Perren, Anja Schmitt, Philippe Krebs, Roch-Philippe Charles, Matthias S Dettmer
Thyroid: Official Journal of the American Thyroid Association 2019 April 2

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human cancers with a median survival of only 3-6 months. Standard treatment options and even targeted therapies have so far failed to improve long-term overall survival. Thus, novel treatment modalities for ATC, such as immunotherapy, are urgently needed. CD47 is a "don't eat me" signal which prevents cancer cells from phagocytosis by binding to signal regulatory protein α (SIRPα) on macrophages. So far, the role of macrophages and the CD47-SIRPα signaling axis in ATC is not well understood.

METHODS: We analyzed 19 primary human ATCs for macrophage markers, CD47 expression and immune checkpoints by immunohistochemistry. ATC cell lines and a fresh ATC sample were assessed by flow cytometry for CD47 expression and macrophage infiltration, respectively. CD47 was blocked in phagocytosis assays of co-cultured macrophages and ATC cell lines. Anti-CD47 antibody treatment was administered to ATC cell line xenotransplanted immunocompromised mice as well as to tamoxifen-induced ATC double-transgenic mice.

RESULTS: Human ATC samples were heavily infiltrated by CD68- and CD163-expressing tumor-associated macrophages (TAMs), and expressed CD47 and calreticulin, the dominant pro-phagocytic molecule. In addition, ATC tissues expressed the immune checkpoint molecules programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1). Blocking CD47 promoted the phagocytosis of ATC cell lines by macrophages in vitro. Anti-CD47 antibody treatment of ATC xenotransplanted mice increased the frequency of TAMs, enhanced the expression of macrophage activation markers, augmented tumor cell phagocytosis, and suppressed tumor growth. In double-transgenic ATC mice, CD47 was expressed on tumor cells and blocking CD47 increased TAM frequencies.

CONCLUSIONS: Targeting CD47 or CD47 in combination with PD-1 may potentially improve the outcomes of ATC patients and may represent a valuable addition to the current standard of care.

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