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Nat Commun ; 11(1): 6335, 2020 12 10.
Article in English | MEDLINE | ID: mdl-33303745

ABSTRACT

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.


Subject(s)
Breast Neoplasms/immunology , CD8-Positive T-Lymphocytes/immunology , Immunity , Receptor Activator of Nuclear Factor-kappa B/metabolism , Signal Transduction , Adult , Animals , Breast Neoplasms/blood , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Line, Tumor , Chemokines/metabolism , Denosumab/pharmacology , Denosumab/therapeutic use , Female , Humans , 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
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