Immunization With RANKL Inhibits Osteolytic Bone Metastasis in Breast Cancer

Breast cancer cells often metastasize to bone. Accumulating evidence suggests that inhibiting the receptor activator of nuclear factor-kappa B ligand (RANKL) not only leads to reduced bone metastasis of breast cancer but also has antitumoral effects. Here, we used mutant receptor activator of nuclear factor-kappa B ligand (RANKL(M)) as a vaccine for active immunization to induce antibodies for immunotherapy of bone metastatic cancer. We investigated whether anti-RANKL antibodies inhibit osteolytic bone metastasis in vitro and in a murine model. MC3T3 cells stimulated by MDA-MB-231 culture medium secreted growth differentiation factor-15 (GDF-15). which induced the nuclear factor-kappa B signaling cascade. In addition. RANKL(M) treatment-induced reduction of intraosseous growth of MDA-MB-231 cells correlated with decreased GDF-15 expression, a reduced number of osteolytic lesions, and slower tumor progression. In addition, vaccination with RANKL(M) led to significant improvement in overall survival and skeletal metastasis in tumor-bearing mice. Induction of anti-RANKL antibodies by RANKL(M) decreased GDF-15 production by deactivating nuclear factor-kappa B signaling, which in turn inhibited metastasis of MDA-MB-231 cells to bone. Taken together, the results demonstrate a role for RANKL(M) immunization in preventing bone metastasis of breast cancer.

Automated summary

In this study, mutant RANKL was used as a vaccine for immunotherapy of bone metastatic breast cancer, and it was found that anti-RANKL antibodies can inhibit intraosseous tumor growth, reduce osteolytic lesions, and improve overall survival and skeletal metastasis in tumor-bearing mice. The induction of anti-RANKL antibodies by RANKL(M) led to decreased GDF-15 production, deactivating the NF-κB signaling pathway and ultimately inhibiting the metastasis of breast cancer cells to bone.