par Gómez-Aleza, Clara;Nguyen, Bastien ;Yoldi, Guillermo;Ciscar, Marina;Barranco, Alexandra;Hernández-Jiménez, Enrique;Maetens, Marion ;Salgado, Roberto;Zafeiroglou, Maria;Pellegrini, Pasquale;Venet, David ;Garaud, Soizic ;Trinidad, Eva Ma;Benítez, Sandra;Vuylsteke, Peter;Polastro, Laura;Wildiers, Hans;Simon, Philippe ;Lindeman, Geoffrey G.J.;Larsimont, Denis ;Van den Eynden, Gert;Velghe, Chloé;Rothé, Françoise ;Willard-Gallo, Karen;Michiels, Stefan ;Muñoz, Purificación;Walzer, Thierry;Planelles, Lourdes;Penninger, Josef;Azim, Hatem A;Loi, Sherene ;Piccart, Martine;Sotiriou, Christos ;González-Suárez, Eva
Référence Nature communications, 11, 1, page (6335)
Publication Publié, 2020-01-01
Référence Nature communications, 11, 1, page (6335)
Publication Publié, 2020-01-01
Article révisé par les pairs
Résumé : | 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. |