期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：1
DOI：10.1073/pnas.2109923118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Tumor-infiltrating macrophages are involved in tumor development, progression, and metastasis. Much recent attention has focused on the modification of macrophage functions in tumors as a basis for cancer treatments. SIRPα and SIRPβ1 are present in macrophages and function as a regulator for phagocytosis. We found that monotherapy with an anti-SIRPα/SIRPβ1 antibody (Ab) suppresses tumor formation by bladder and mammary cancer cells in mice. This effect is likely mediated by promoting the cytotoxic and phagocytic activity of macrophages against tumor cells. Notably, the antitumor effect of the Ab is largely dependent on its binding to SIRPβ1 on macrophages. Our findings reveal mechanisms of antitumor action of the anti-SIRPα/SIRPβ1 Ab and targeting of SIRPβ1 as a potential strategy for cancer immunotherapy.
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.
