CD47‐signal regulatory protein α signaling system and its application to cancer immunotherapy

• Published in: Cancer science Vol. 109; no. 8; pp. 2349 - 2357
• Main Authors: Murata, Yoji, Saito, Yasuyuki, Kotani, Takenori, Matozaki, Takashi
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.08.2018
• Subjects: Adaptive Immunity - immunology; Animals; cancer immunotherapy; CD47; CD47 Antigen - immunology; Humans; Immunotherapy - methods; macrophage; Neoplasms - immunology; Neoplasms - therapy; phagocytosis; Receptors, Immunologic - immunology; Review; signal regulatory protein α (SIRPα); phagocytosis; macrophage; CD47; signal regulatory protein α (SIRPα); cancer immunotherapy
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.13663

Tumor cells evade immune surveillance through direct or indirect interactions with various types of immune cell, with much recent attention being focused on modifying immune cell responses as the basis for the development of new cancer treatments. Signal regulatory protein α (SIRPα) and CD47 are both transmembrane proteins that interact with each other and constitute a cell‐cell communication system. SIRPα is particularly abundant in myeloid cells such as macrophages and dendritic cells, whereas CD47 is expressed ubiquitously and its expression level is elevated in cancer cells. Recent studies have shown that blockade of CD47‐SIRPα interaction enhances the phagocytic activity of phagocytes such as macrophages toward tumor cells in vitro as well as resulting in the efficient eradication of tumor cells in a variety of xenograft or syngeneic mouse models of cancer. Moreover, CD47 blockade has been shown to promote the stimulation of tumor‐specific cytotoxic T cells by macrophages or dendritic cells. Biological agents, such as Abs and recombinant proteins, that target human CD47 or SIRPα have been developed and are being tested in preclinical models of human cancer or in clinical trials with cancer patients. Preclinical studies have also suggested that CD47 or SIRPα blockade may have a synergistic antitumor effect in combination with immune checkpoint inhibitors that target the adaptive immune system. Targeting of the CD47‐SIRPα signaling system is thus a promising strategy for cancer treatment based on modulation of both innate and acquired immune responses to tumor cells. Direct interaction of tumor cells with immune cells is involved in tumor evasion from the immune system. Interaction of CD47 on tumor cells with SIRPα on phagocytes, such as macrophages, serves as an innate immune checkpoint that attenuates phagocyte‐mediated antitumor immune responses. This article reviews the role of the CD47‐SIRPα signaling system in cancer immune surveillance, and therapeutic approaches targeting this system in cancer.