DLL1-responsive PD-L1⁺ tumor-associated macrophages promote endocrine resistance in breast cancer

Estrogen receptor–positive (ER+) luminal breast cancer comprises 75resistant luminal breast cancer remains unclear. This limitation is due in part to a lack of immunocompetent preclinical models investigating the comprehensive involvement of immune cells in the tumor microenvironment (TME) in the context of endocrine resistance. In this study, we identified a subtype of immunosuppressive (M2-like) programmed death ligand 1–positive (PD-L1+) tumor-associated macrophages (TAMs) critically fostering resistance to tamoxifen (TMX) and fulvestrant (FV) through maintaining cancer stem cell (CSC) activity in new mouse models. These TAMs are recruited by Delta-like ligand 1 (DLL1), a Notch signaling ligand expressed in luminal tumor cells, through the CCR3/CCL7 axis. Combination therapy with anti-DLL1 and anti–PD-L1 antibodies with TMX reduced tumor growth and associated CSCs and reprogrammed the immunosuppressive TME in both preclinical mouse models and patient-derived explants, thus laying the foundation for a future combined immune-endocrine therapy in these patients. Triple combination therapy reverses endocrine resistance driven by DLL1high tumor cells, which recruit immunosuppressive PD-L1+ TAMs sustaining CSCs. Patients with estrogen receptor–positive (ER+) luminal breast cancer benefit from targeted ER therapy; however, many patients often have de novo or acquired resistance and require additional treatment. Here, Singh etnbsp;al. explore the use of immunotherapy in mouse models and patients with ER+ breast cancer to overcome resistance. They identify PD-L1+ tumor-associated macrophages that are immunosuppressive and are dependent on Delta-like ligand–positive (DLL1+) tumor cells for recruitment and polarization to M2 type. The authors combine targeting of DLL1 with PD-L1 alongside tamoxifen (TMX) to overcome resistance in preclinical mouse models and patient-derived explants. This presents a promising new avenue of treatment that requires further exploration. —Dorothy Hallberg