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

TY - JOUR

T1 - Targeting CD47 in anaplastic thyroid carcinoma enhances tumor phagocytosis by macrophages and is a promising therapeutic strategy

AU - Schürch, Christian M

AU - Roelli, Matthias A

AU - Forster, Stefan

AU - Wasmer, Marie-Hélène

AU - Brühl, Frido

AU - Maire, Renaud

AU - Di Pancrazio, Sergio

AU - Ruepp, Marc-David

AU - Giger, Roland

AU - Perren, Aurel

AU - Schmitt, Anja

AU - Krebs, Philippe

AU - Charles, Roch-Philippe

AU - Dettmer, Matthias S

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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.

KW - CD47

KW - anaplastic thyroid carcinoma

KW - immune checkpoints

KW - phagocytosis

KW - programmed cell death 1

KW - tumor-associated macrophages

UR - http://www.scopus.com/inward/record.url?scp=85069197042&partnerID=8YFLogxK

U2 - 10.1089/thy.2018.0555

DO - 10.1089/thy.2018.0555

M3 - Article

C2 - 30938231

SN - 1050-7256

VL - 29

SP - 979

EP - 992

JO - Thyroid

JF - Thyroid

IS - 7

ER -