Targeting CD47 in Anaplastic Thyroid Carcinoma Enhances Tumor Phagocytosis by Macrophages and Is a Promising Therapeutic Strategy.

Schürch, Christian M; Rölli, Matthias A.; Forster, Stefan; Wasmer, Marie-Hélène; Brühl, Frido; Maire, Renaud S.; Di Pancrazio, Sergio; Ruepp, Marc-David; Giger, Roland; Perren, Aurel; Schmitt, Anja M.; Krebs, Philippe; Charles, Roch-Philippe; Dettmer, Matthias S. (2019). Targeting CD47 in Anaplastic Thyroid Carcinoma Enhances Tumor Phagocytosis by Macrophages and Is a Promising Therapeutic Strategy. Thyroid, 29(7), pp. 979-992. Mary Ann Liebert 10.1089/thy.2018.0555

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Background:
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human cancers, with a median survival of only three to six 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 alpha on macrophages. So far, the role of macrophages and the CD47-signal regulatory protein alpha signaling axis in ATC is not well understood.
Methods:
This study 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 and programmed death ligand 1. 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 programmed cell death 1 may potentially improve the outcomes of ATC patients and may represent a valuable addition to the current standard of care.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Ear, Nose and Throat Disorders (ENT)
04 Faculty of Medicine > Service Sector > Institute of Pathology > Molecular Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Service Sector > Institute of Pathology
08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)
04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology

UniBE Contributor:

Rölli, Matthias Andreas; Forster, Stefan; Wasmer, Marie-Hélène Christin; Brühl, Frido; Maire, Renaud Sylvain; Ruepp, Marc-David; Giger, Roland; Perren, Aurel; Schmitt Kurrer, Anja; Krebs, Philippe; Charles, Roch-Philippe and Dettmer, Matthias

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
500 Science > 540 Chemistry

ISSN:

1050-7256

Publisher:

Mary Ann Liebert

Language:

English

Submitter:

Matthias Dettmer

Date Deposited:

25 Sep 2019 10:44

Last Modified:

23 Oct 2019 05:38

Publisher DOI:

10.1089/thy.2018.0555

PubMed ID:

30938231

Uncontrolled Keywords:

CD47 anaplastic thyroid carcinoma immune checkpoints phagocytosis programmed cell death 1 tumor-associated macrophages

BORIS DOI:

10.7892/boris.133286

URI:

https://boris.unibe.ch/id/eprint/133286

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