Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells.
(2020) Nature Communications — Vol. 11, n° 1, p. 6335 [1-18] (2020)
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Gómez-Aleza, Clara 
Nguyen, Bastien González-Suárez, Eva
- 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.
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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., et al. (2020). Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells. Nature Communications, 11(1), 6335 [1-18]. https://doi.org/10.1038/s41467-020-20138-8 (Original work published 2020)