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

The interaction of signal regulatory protein a (SIRP alpha) 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-SIRP alpha interaction by Abs to CD47 or to SIRP alpha 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 SIRP alpha that also recognizes SIRP beta 1 inhibited tumor formation by bladder and mammary cancer cells in mice, with this inhibitory effect being largely dependent on macrophages. The mAb to SIRP alpha promoted polarization of tumor-infiltrating macrophages toward an antitumorigenic phenotype, resulting in the killing and phagocytosis of cancer cells by the macrophages. Ablation of SIRP alpha in mice did not prevent the inhibitory effect of the anti-SIRP alpha mAb on tumor formation or its promotion of the cancer cell-killing activity of macrophages, however. Moreover, knockdown of SIRP beta 1 in macrophages attenuated the stimulatory effect of the anti-SIRP alpha mAb on the killing of cancer cells, whereas an mAb specific for SIRP beta 1 mimicked the effect of the anti-SIRP alpha mAb. Our results thus suggest that monotherapy with Abs to SIRP alpha/SIRP beta 1 induces antitumorigenic macrophages and thereby inhibits tumor growth and that SIRP beta 1 is a potential target for cancer immunotherapy.

Automated summary

Monotherapy with antibodies targeting SIRP alpha/SIRP beta 1 can induce antitumorigenic macrophages and inhibit tumor growth by promoting killing and phagocytosis of cancer cells by these macrophages. Therefore, SIRP beta 1 is a potential target for cancer immunotherapy.