Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells

Nat Commun. 2020 Dec 10;11(1):6335. doi: 10.1038/s41467-020-20138-8.


Most breast cancers exhibit low immune infiltration and are unresponsive to immunotherapy. We hypothesized that inhibition of the receptor activator of nuclear factor-κB (RANK) signaling pathway may enhance immune activation. Here we report that loss of RANK signaling in mouse tumor cells increases leukocytes, lymphocytes, and CD8+ T cells, and reduces macrophage and neutrophil infiltration. CD8+ T cells mediate the attenuated tumor phenotype observed upon RANK loss, whereas neutrophils, supported by RANK-expressing tumor cells, induce immunosuppression. RANKL inhibition increases the anti-tumor effect of immunotherapies in breast cancer through a tumor cell mediated effect. Comparably, pre-operative single-agent denosumab in premenopausal early-stage breast cancer patients from the Phase-II D-BEYOND clinical trial (NCT01864798) is well tolerated, inhibits RANK pathway and increases tumor infiltrating lymphocytes and CD8+ T cells. Higher RANK signaling activation in tumors and serum RANKL levels at baseline predict these immune-modulatory effects. No changes in tumor cell proliferation (primary endpoint) or other secondary endpoints are observed. Overall, our preclinical and clinical findings reveal that tumor cells exploit RANK pathway as a mechanism to evade immune surveillance and support the use of RANK pathway inhibitors to prime luminal breast cancer for immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Breast Neoplasms / blood
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / immunology*
  • Breast Neoplasms / pathology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Chemokines / metabolism
  • Denosumab / pharmacology
  • Denosumab / therapeutic use
  • Female
  • Humans
  • Immunity*
  • Immunosuppression Therapy
  • Immunotherapy
  • Inflammation Mediators / metabolism
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice, Inbred C57BL
  • Middle Aged
  • Models, Biological
  • Myeloid Cells / immunology
  • Neoplasm Staging
  • Neutrophils / immunology
  • RANK Ligand / blood
  • RANK Ligand / metabolism
  • Receptor Activator of Nuclear Factor-kappa B / metabolism*
  • Signal Transduction*


  • Chemokines
  • Inflammation Mediators
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Denosumab

Associated data