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

Thyroid. 2019 Jul;29(7):979-992. doi: 10.1089/thy.2018.0555. Epub 2019 May 10.

Abstract

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.

Keywords: CD47; anaplastic thyroid carcinoma; immune checkpoints; phagocytosis; programmed cell death 1; tumor-associated macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Antigens, Differentiation / immunology*
  • Antigens, Differentiation / metabolism
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism
  • CD47 Antigen / antagonists & inhibitors
  • CD47 Antigen / immunology*
  • CD47 Antigen / metabolism
  • Cell Line, Tumor
  • Female
  • Humans
  • Immunohistochemistry
  • Immunotherapy
  • In Vitro Techniques
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Molecular Targeted Therapy
  • Neoplasm Transplantation
  • Phagocytosis / immunology*
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptors, Immunologic / immunology*
  • Receptors, Immunologic / metabolism
  • Thyroid Carcinoma, Anaplastic / immunology*
  • Thyroid Carcinoma, Anaplastic / metabolism
  • Thyroid Neoplasms / immunology*
  • Thyroid Neoplasms / metabolism
  • Tumor Escape / immunology*
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, Differentiation
  • B7-H1 Antigen
  • CD274 protein, human
  • CD47 Antigen
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic
  • SIRPA protein, human