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Inhibition of RANK Signaling in Breast Cancer Induces an Anti-Tumor Immune Response Orchestrated by CD8+ T Cells

Authors: Clara Gómez-Aleza, Bastien Nguyen, Guillermo Yoldi, Marina Ciscar, Alexandra Barranco, Enrique Hernández-Jiménez, Marion Maetens, Roberto Salgado, Maria Zafeiroglou, Pasquale Pellegrini, David Venet, Soizic Garaud, Eva M. Trinidad, Sandra Benítez, Peter Vuylsteke, Laura Polastro, Hans Wildiers, Philippe Simon, Geoffrey Lindeman, Denis Larsimont, Gert Van den Eynden, Chloé Velghe, Françoise Rothé, Karen Willard-Gallo, Stefan Michiels, Purificación Muñoz, Thierry Walzer, Lourdes Planelles, Josef Penninger, Hatem A. Azim Jr, Sherene Loi, Martine Piccart, Christos Sotiriou & Eva González-Suárez

Online: https://www.nature.com/articles/s41467-020-20138-8

Issue: Nat Commun. 2020 Dec 10;11(1):6335.


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.