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- Title
Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells.
- Authors
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 M.; Benítez, Sandra; Vuylsteke, Peter; Polastro, Laura; Wildiers, Hans; Simon, Philippe; Lindeman, Geoffrey; Larsimont, Denis
- 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. Receptor activator of nuclear factor-κB (RANK)/RANK-ligand (RANKL) signaling regulates the tumor-immune crosstalk. Here the authors show that systemic RANKL inhibition promotes CD8 + T cell infiltration in patients with early breast cancer and that loss of RANK signaling in tumor cells drives a T cell-dependent anti-tumor response in preclinical models.
- Subjects
T cells; BREAST cancer; IMMUNE response; TRANCE protein; ANIMAL models in research; NEUTROPHILS; CYTOTOXIC T cells
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-20138-8