Anticancer efficacy of monotherapy with antibodies to SIRPα/SIRPβ1 mediated by induction of antitumorigenic macrophages.

Abstract

The interaction of signal regulatory protein α (SIRPα) on macrophages with CD47 on cancer cells is thought to prevent antibody (Ab)-dependent cellular phagocytosis (ADCP) of the latter cells by the former. Blockade of the CD47-SIRPα interaction by Abs to CD47 or to SIRPα, in combination with tumor-targeting Abs such as rituximab, thus inhibits tumor formation by promoting macrophage-mediated ADCP of cancer cells. Here we show that monotherapy with a monoclonal Ab (mAb) to SIRPα that also recognizes SIRPβ1 inhibited tumor formation by bladder and mammary cancer cells in mice, with this inhibitory effect being largely dependent on macrophages. The mAb to SIRPα promoted polarization of tumor-infiltrating macrophages toward an antitumorigenic phenotype, resulting in the killing and phagocytosis of cancer cells by the macrophages. Ablation of SIRPα in mice did not prevent the inhibitory effect of the anti-SIRPα mAb on tumor formation or its promotion of the cancer cell-killing activity of macrophages, however. Moreover, knockdown of SIRPβ1 in macrophages attenuated the stimulatory effect of the anti-SIRPα mAb on the killing of cancer cells, whereas an mAb specific for SIRPβ1 mimicked the effect of the anti-SIRPα mAb. Our results thus suggest that monotherapy with Abs to SIRPα/SIRPβ1 induces antitumorigenic macrophages and thereby inhibits tumor growth and that SIRPβ1 is a potential target for cancer immunotherapy.

• Authors: Mariko Sakamoto, Yoji Murata, Daisuke Tanaka, Yuka Kakuchi, Takeshi Okamoto, Daisuke Hazama, Yasuyuki Saito, Takenori Kotani, Hiroshi Ohnishi, Masayuki Miyasaka, Masato Fujisawa, Takashi Matozaki
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 119 Issue 1 (01 04 2022) ISSN: 1091-6490 [Electronic] United States
• PMID: 34949714 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 the Author(s). Published by PNAS.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Antineoplastic Agents, Immunological
• CD47 Antigen
• Ptpns1 protein, mouse
• Receptors, Cell Surface
• Receptors, Immunologic
• Rituximab

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antineoplastic Agents (pharmacology)
• Antineoplastic Agents, Immunological (pharmacology)
• CD47 Antigen (metabolism)
• Cell Line, Tumor
• Immunotherapy (methods)
• Macrophages (metabolism)
• Mice
• Receptors, Cell Surface (genetics, metabolism)
• Receptors, Immunologic (genetics, metabolism)
• Rituximab
• Treatment Outcome
• Urinary Bladder