Katherine Alexander

Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) can be polarized to anti-tumor M1-like or pro-tumor M2-like differentiated states. This phenotypic balance impacts the efficacy of immune checkpoint blockade (ICB). We demonstrated that a neutralizing antibody specifically targeting Notch4 reduced breast tumor growth with no apparent toxicity, improving upon prior broad-acting Notch inhibitors. We show that Notch4 blockade expands anti-tumor TAMs and reduces M2-like polarization in vivo and in vitro. We will expand these findings to include the effects of a newly developed Notch4 decoy peptibody. Using preclinical mouse models, we will test the mechanism of action of Notch4 blockade by characterizing Notch peptibody effects on M2-like polarization in primary macrophages. We will pharmacologically inhibit Notch4 with the Notch4 decoy peptibody to examine the anti-tumor potential of TAMs and the efficacy of ICB therapy in combination with Notch4 blockade.