Effects of a humanized CD47 antibody and recombinant SIRPα proteins on triple negative breast carcinoma stem cells

Sukhbir Kaur; Bianca Reginauld; Sam Razjooyan; Trung Phi; Satya P Singh; Thomas J Meyer; Margaret C Cam; David D Roberts

doi:10.3389/fcell.2024.1356421

Effects of a humanized CD47 antibody and recombinant SIRPα proteins on triple negative breast carcinoma stem cells

Front Cell Dev Biol. 2024 Mar 1:12:1356421. doi: 10.3389/fcell.2024.1356421. eCollection 2024.

Authors

Sukhbir Kaur¹, Bianca Reginauld¹, Sam Razjooyan¹, Trung Phi¹, Satya P Singh², Thomas J Meyer³, Margaret C Cam³, David D Roberts¹

Affiliations

¹ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
² Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
³ CCR Collaborative Bioinformatics, Resource, Office of Science and Technology Resources, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.

Abstract

Signal regulatory protein-α (SIRPα, SHPS-1, CD172a) expressed on myeloid cells transmits inhibitory signals when it engages its counter-receptor CD47 on an adjacent cell. Elevated CD47 expression on some cancer cells thereby serves as an innate immune checkpoint that limits phagocytic clearance of tumor cells by macrophages and antigen presentation to T cells. Antibodies and recombinant SIRPα constructs that block the CD47-SIRPα interaction on macrophages exhibit anti-tumor activities in mouse models and are in ongoing clinical trials for treating several human cancers. Based on prior evidence that engaging SIRPα can also alter CD47 signaling in some nonmalignant cells, we compared direct effects of recombinant SIRPα-Fc and a humanized CD47 antibody that inhibits CD47-SIRPα interaction (CC-90002) on CD47 signaling in cancer stem cells derived from the MDA-MB- 231 triple-negative breast carcinoma cell line. Treatment with SIRPα-Fc significantly increased the formation of mammospheres by breast cancer stem cells as compared to CC-90002 treatment or controls. Furthermore, SIRPα-Fc treatment upregulated mRNA and protein expression of ALDH1 and altered the expression of genes involved in epithelial/mesenchymal transition pathways that are associated with a poor prognosis and enhanced metastatic activity. This indicates that SIRPα-Fc has CD47-mediated agonist activities in breast cancer stem cells affecting proliferation and metastasis pathways that differ from those of CC-90002. This SIRPα-induced CD47 signaling in breast carcinoma cells may limit the efficacy of SIRPα decoy therapeutics intended to stimulate innate antitumor immune responses.

Keywords: CD47; EMT; SIRPα; breast cancer; cancer stem cells.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (DDR, ZIA SC009172) and Cooperative Research and Development Agreement 03083 with Celgene, which provided CC90002 and control antibodies and funding for reagents and salary support for SR. Celgene was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.