Gómez-Aleza, ClaraNguyen, BastienYoldi, GuillermoCiscar, MarinaBarranco, AlexandraHernández-Jiménez, EnriqueMaetens, MarionSalgado, RobertoZafeiroglou, MariaPellegrini, PasqualeVenet, DavidGaraud, SoizicTrinidad, Eva MBenítez, SandraVuylsteke, PeterPolastro, LauraWildiers, HansSimon, PhilippeLindeman, GeoffreyLarsimont, DenisVan den Eynden, GertVelghe, ChloéRothé, FrançoiseWillard-Gallo, KarenMichiels, StefanMuñoz, PurificaciónWalzer, ThierryPlanelles, LourdesPenninger, JosefAzim, Hatem ALoi, SherenePiccart, MartineSotiriou, ChristosGonzález-Suárez, Eva2021-03-092021-03-092020-11-11Nat Commun. 2020;11(1):6335.http://hdl.handle.net/20.500.12105/12178Most 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.engVoRhttp://creativecommons.org/licenses/by-nc-sa/4.0/ImmunitySignal TransductionAdultAnimalsBreast NeoplasmsCD8-Positive T-LymphocytesCell Line, TumorChemokinesDenosumabFemaleHumansImmunosuppressionImmunotherapyInflammation MediatorsLymphocytes, Tumor-InfiltratingMice, Inbred C57BLMiddle AgedModels, BiologicalMyeloid CellsNeoplasm StagingNeutrophilsRANK LigandReceptor Activator of Nuclear Factor-kappa BAtribución-NoComercial-CompartirIgual 4.0 Internacional33303745111633510.1038/s41467-020-20138-82041-1723Nature communicationsopen access