Sakamoto et al. studied the antitumor mechanism of mAb M1, which binds murine SIRPα and SIRPβ1 on myeloid cells and blocks the interaction of SIRPα with CD47 on cancer cells. Monotherapy with M1 inhibited growth of bladder and mammary cancer cells in immunocompetent mice by promotion of macrophage-mediated phagocytosis and killing and by polarization of tumor-infiltrating macrophages towards a TNFα-expressing anti-tumorigenic M1-like phenotype. SIRPα ablation had no effect on efficacy, whereas knockdown of SIRβ1 in macrophages attenuated M1 activity, revealing SIRPβ1 as a potential cancer target.
Contributed by Katherine Turner
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.
Author Info: (1) Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. Division of U
Author Info: (1) Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. Division of Urology, Department of Surgery Related, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. (2) Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; ymurata@med.kobe-u.ac.jp matozaki@med.kobe-u.ac.jp. (3) Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. (4) Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. (5) Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. (6) Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. (7) Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. (8) Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. (9) Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Gunma 371-8514, Japan. (10) Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. (11) Division of Urology, Department of Surgery Related, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. (12) Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; ymurata@med.kobe-u.ac.jp matozaki@med.kobe-u.ac.jp.
