Inhibition of RANK signaling interferes with macrophages' immunosuppressive role enhancing tumor immunity in breast adenocarcinomas

ABSTRACT: Luminal breast tumors generally exhibit low immune infiltration and are unresponsive to immunotherapy. The inhibitor of Receptor Activator of NFkB (RANK) signaling pathway, denosumab, has emerged as putative therapeutic in breast cancer, for its pleiotropic effects on cancer and immune cells. Previous results demonstrate that RANK signaling activation in luminal tumor cells enhances stemness and immunosuppression. In breast adenocarcinomas RANK is also expressed in tumor-associated macrophages (TAMs), but whether and how RANK influences macrophage phenotype and functionality and its impact on tumor outcome remains unknown. Here we present a comprehensive characterization of the immunomodulatory effects of neoadjuvant denosumab in patients with early-stage luminal breast cancer from the D-BIOMARK clinical trial (NCT03691311). Transcriptomic and proteomic analyses revealed that preoperative denosumab treatment reduces the presence of immunosuppressive macrophages, increases the expression of monocyte-related genes, and activates pathways associated with innate and adaptive immune responses. Mechanistic studies in preclinical models reveal that Rank genetic loss in macrophages delays tumor onset through the induction of a pro-inflammatory TAM profile that enhances anti-tumor immunity. Complementary pharmacological treatments with Rankl inhibitors disrupt the immunosuppressive function of TAMs and attenuate tumorigenesis. Finally, we identify levels of CCL8 and the presence of immune-suppressive TAMs at baseline, as biomarkers to select the population of D-BIOMARK patients with greater response to denosumab-driven immune changes. Together, our preclinical and clinical data underscore the potential of RANK pathway inhibitors as immunomodulatory therapeutics in luminal breast cancer and allow the selection of patients who can benefit from denosumab treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291079 | GEO | 2026/03/03

REPOSITORIES: GEO