2026-04-29T12:23:01Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/121782024-11-29T20:58:05Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Gómez-Aleza, Clara author Nguyen, Bastien author Yoldi, Guillermo author Ciscar, Marina author Barranco, Alexandra author Hernández-Jiménez, Enrique author Maetens, Marion author Salgado, Roberto author Zafeiroglou, Maria author Pellegrini, Pasquale author Venet, David author Garaud, Soizic author Trinidad, Eva M author Benítez, Sandra author Vuylsteke, Peter author Polastro, Laura author Wildiers, Hans author Simon, Philippe author Lindeman, Geoffrey author Larsimont, Denis author Van den Eynden, Gert author Velghe, Chloé author Rothé, Françoise author Willard-Gallo, Karen author Michiels, Stefan author Muñoz, Purificación author Walzer, Thierry author Planelles, Lourdes author Penninger, Josef author Azim, Hatem A author Loi, Sherene author Piccart, Martine author Sotiriou, Christos author González-Suárez, Eva author 2020-11-11 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. Nat Commun. 2020;11(1):6335. 10.1038/s41467-020-20138-8 2041-1723 Nature communications 33303745 http://hdl.handle.net/20.500.12105/12178 Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells.