Background: HER2 overexpression define ~20% of breast cancers (BC) that are currently treated using HER2-specific monoclonal antibodies (mAb), such as Trastuzumab. While multiple studies have confirmed Trastuzumab’s anti-tumor efficacy, its dominant immune mechanism of therapeutic action (MOA) remains unclear. As Trastuzumab efficacy is subverted in advanced immunosuppressive cancers, an understanding of its MOA and strategy to boost its therapeutic effect is of clinical interest and scientific significance for immunologically enhancing targeted mAb treatments.
Results: We found that Trastuzumab significantly suppressed tumor growth and stimulated the infiltration of tumor-associated-macrophages (TAMs). Importantly, this anti-tumor activity did not require adaptive immunity or NK cells, but did require FcγR engagement, implicating macrophages as the dominant immune effector. Consistently, we demonstrated Trastuzumab activates FcγR4 signaling and elicited significant macrophage-mediated phagocytosis (ADCP) of HER2+ BC. To test if enhanced ADCP could confer more effective anti-tumor immunity, we combined Trastuzumab with blockade of the ADCP checkpoint, CD47 (“don’t eat me signal”), and found that this combination significantly increased Trastuzumab-mediated ADCP. Critically, we also found that this combination enhanced TAM infiltration in vivo, as well as stimulated stronger anti-tumor efficacy and prolonged survival in highly immunosuppressive tumor microenvironments.
Conclusion: Our study demonstrates the major MOA of clinically relevant HER2 mAbs requires the engagement with TAMs to elicit ADCP of tumor cells, which could be significantly enhanced by CD47 blockade. We conclude CD47 blockade could unleash the full potential of HER2 mAb therapy by abrogating the innate immunosuppressive signals on macrophages to stimulate immunity and enhance anti-tumor efficacy.