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

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 Eynden, Chloé Velghe, Françoise Rothé, Karen Willard-Gallo, Stefan Michiels, Purificación Muñoz, Thierry Walzer, Lourdes Planelles, Josef Penninger, Hatem A. Azim, Sherene Loi, Martine Piccart, Christos Sotiriou () and Eva González-Suárez ()
Additional contact information
Clara Gómez-Aleza: Bellvitge Biomedical Research Institute, IDIBELL
Bastien Nguyen: Université Libre de Bruxelles
Guillermo Yoldi: Bellvitge Biomedical Research Institute, IDIBELL
Marina Ciscar: Bellvitge Biomedical Research Institute, IDIBELL
Alexandra Barranco: Bellvitge Biomedical Research Institute, IDIBELL
Enrique Hernández-Jiménez: Bellvitge Biomedical Research Institute, IDIBELL
Marion Maetens: Université Libre de Bruxelles
Roberto Salgado: Université Libre de Bruxelles
Maria Zafeiroglou: Bellvitge Biomedical Research Institute, IDIBELL
Pasquale Pellegrini: Bellvitge Biomedical Research Institute, IDIBELL
David Venet: Université Libre de Bruxelles
Soizic Garaud: Université Libre de Bruxelles
Eva M. Trinidad: Bellvitge Biomedical Research Institute, IDIBELL
Sandra Benítez: Bellvitge Biomedical Research Institute, IDIBELL
Peter Vuylsteke: Université Catholique de Louvain, CHU UCL, Namur, site Sainte-Elisabeth
Laura Polastro: Université Libre de Bruxelles
Hans Wildiers: KU Leuven-University of Leuven
Philippe Simon: Université Libre de Bruxelles
Geoffrey Lindeman: The Walter and Eliza Hall Institute of Medical Research and The Royal Melbourne Hospital
Denis Larsimont: Université Libre de Bruxelles
Gert Eynden: Université Libre de Bruxelles
Chloé Velghe: Université Libre de Bruxelles
Françoise Rothé: Université Libre de Bruxelles
Karen Willard-Gallo: Université Libre de Bruxelles
Stefan Michiels: Université Paris-Saclay
Purificación Muñoz: Bellvitge Biomedical Research Institute, IDIBELL
Thierry Walzer: Université Claude Bernard
Lourdes Planelles: Parc Cientific Universitat
Josef Penninger: University of British Columbia
Hatem A. Azim: American University of Beirut
Sherene Loi: The Walter and Eliza Hall Institute of Medical Research and The Royal Melbourne Hospital
Martine Piccart: Université Libre de Bruxelles
Christos Sotiriou: Université Libre de Bruxelles
Eva González-Suárez: Bellvitge Biomedical Research Institute, IDIBELL

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-20138-8

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