2026-04-29T12:23:07Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/121782024-11-29T20:58:05Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
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
funder
Institut Jules Bordet
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Fundación La Marató TV3
funder
National Fund for Research (Francia)
funder
Breast Cancer Research Foundation
2021-03-09T15:07:29Z
2021-03-09T15:07:29Z
2020-11-11
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
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.
eng
Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells.
journal article
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