Exploring the role of the receptor activator of nuclear factor-κB (RANK) pathway in breast cancer, Aleza, Nguyen, and Yoldi et al. demonstrated in the PyMT mammary tumor model that blocking the tumor cell RANK pathway increases CD8+ T cell infiltration and reduces immunosuppressive neutrophil accumulation in tumors. Anti-RANKL antibody therapy results in improved survival, which is enhanced by ICB. In a clinical trial of an anti-RANKL Ab in pre-surgical breast cancer, similar favorable changes in T cell infiltration were observed, and serum (solRANKL), IHC (Treg), and biopsy (RNASeq) prognostic markers were identified.
Contributed by Ed Fritsch
ABSTRACT: Most breast cancers exhibit low immune infiltration and are unresponsive to immunotherapy. We hypothesized that inhibition of the receptor activator of nuclear factor-_B (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.