Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells
- 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, EM; 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, HA, Jr; Loi, S; Piccart, M; Sotiriou, C; González-Suárez, E;
Publication Year 2020-12-10, Volume 11, Issue #1, Page 6335
- Journal Title
- Nature Communications
- Publication Type
- Journal Article
- 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.
- WEHI Research Division(s)
- Cancer Biology And Stem Cells
- PubMed ID
- Publisher's Version
- Open Access at Publisher's Site
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2021-02-01 12:08:29Last Modified: 2021-02-23 03:05:52