Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells Journal Article

Authors: Gómez-Aleza, C.; Nguyen, B.; Yoldi, G.; Ciscar, M.; Barranco, A.; Hernández-Jiménez, E.; Maetens, M.; Salgado, R.; Zafeiroglou, M.; Pellegrini, P.; Venet, D.; Garaud, S.; Trinidad, E. M.; Benítez, S.; Vuylsteke, P.; Polastro, L.; Wildiers, H.; Simon, P.; Lindeman, G.; Larsimont, D.; Van den Eynden, G.; Velghe, C.; Rothé, F.; Willard-Gallo, K.; Michiels, S.; Muñoz, P.; Walzer, T.; Planelles, L.; Penninger, J.; Azim, H. A. Jr; Loi, S.; Piccart, M.; Sotiriou, C.; González-Suárez, E.
Article Title: Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells
Abstract: 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. © 2020, The Author(s).
Keywords: immune system; signaling; immune response; tumor; serum; biological development; inhibition; cancer
Journal Title: Nature Communications
Volume: 11
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2020-12-10
Start Page: 6335
Language: English
DOI: 10.1038/s41467-020-20138-8
PUBMED: 33303745
PROVIDER: scopus
PMCID: PMC7728758
Notes: Article -- Export Date: 4 January 2021 -- Source: Scopus
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MSK Authors
  1. Bastien Nguyen
    26 Nguyen