CD47 blockade enhances the efficacy of intratumoral STING-targeting therapy by activating phagocytes
Open Access
- 24 September 2021
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 218 (11)
- https://doi.org/10.1084/jem.20200792
Abstract
Activation of STING signaling plays an important role in anti-tumor immunity, and we previously reported the anti-tumor effects of STING through accumulation of M1-like macrophages in tumor tissue treated with a STING agonist. However, myeloid cells express SIRPα, an inhibitory receptor for phagocytosis, and its receptor, CD47, is overexpressed in various cancer types. Based on our findings that breast cancer patients with highly expressed CD47 have poor survival, we evaluated the therapeutic efficacy and underlying mechanisms of combination therapy with the STING ligand cGAMP and an antagonistic anti-CD47 mAb using E0771 mouse breast cancer cells. Anti-CD47 mAb monotherapy did not suppress tumor growth in our setting, whereas cGAMP and anti-CD47 mAb combination therapy inhibited tumor growth. The combination therapy enhanced phagocytosis of tumor cells and induced systemic anti-tumor immune responses, which rely on STING and type I IFN signaling. Taken together, our findings indicate that coadministration of cGAMP and an antagonistic anti-CD47 mAb may be promising for effective cancer immunotherapy.Keywords
Funding Information
- Japan Society for the Promotion of Science (JP17K15633)
- Akiyama Life Science Foundation
- Suhara Memorial Foundation
- Hokkaido University
This publication has 51 references indexed in Scilit:
- The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumorsProceedings of the National Academy of Sciences of the United States of America, 2012
- CD47–signal regulatory protein-α (SIRPα) interactions form a barrier for antibody-mediated tumor cell destructionProceedings of the National Academy of Sciences of the United States of America, 2011
- Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cellsThe Journal of Experimental Medicine, 2011
- Type I interferon is selectively required by dendritic cells for immune rejection of tumorsThe Journal of Experimental Medicine, 2011
- Anti-CD47 Antibody Synergizes with Rituximab to Promote Phagocytosis and Eradicate Non-Hodgkin LymphomaCell, 2010
- STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunityNature, 2009
- CD47 Is an Adverse Prognostic Factor and Therapeutic Antibody Target on Human Acute Myeloid Leukemia Stem CellsCell, 2009
- A type I interferon autocrine–paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cellsThe Journal of Experimental Medicine, 2005
- Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumorsThe Journal of Experimental Medicine, 2005
- Role of CD47 as a Marker of Self on Red Blood CellsScience, 2000