RANKL: a promising target for cancer immunotherapy
A study conducted by researchers from the Laboratory of Experimental Pathology at ULiege (GIGA institute) demonstrates that, besides promoting cancer progression through its well-described role as a chemotactic factor to attract malignant cells to bones, the protein RANKL has a strong immunosuppressive action on antigen-presenting cells [dendritic cells (DC)/plasmacytoid dendritic cells (pDC)]. These results are published in Journal for ImmunoTherapy of Cancer.
Initially identified for its involvement in bone formation/remodeling, the RANKL/RANK axis is now recognized for its effects that go far beyond bone biology. In cancer development and spread, while its direct impact on tumor cells is well described, the influence of the RANKL/RANK ligand-receptor (and its inhibition) on intratumoral immune cells remained insufficiently explored.
This study conducted by Michael Herfs (FNRS Research Associate), Pascale Hubert (Senior First Assistant, ULiège) and their team highlights the strong immunosuppressive function of RANKL in tumor microenvironment. “We used various RANKL inhibitors and a significant decrease in tumor growth, which was further enhanced by neoadjuvant chemotherapy, was consistently observed in syngeneic mouse models of triple-negative breast cancer” explains Pascale Hubert.
“Importantly, the therapeutic efficacy of RANKL blockade was not detected in immunocompromised models, illustrating that this anti-tumor effect was dependent on the adaptive immune system”, adds Michael Herfs.
“From a mechanistic point of view, our in vivo/in vitro results show that RANKL promotes T regulatory cell differentiation and suppressive function in tumor microenvironment through acting as a tolerogenic signal on antigen-presenting cells (DC/pDC). These results could also explain the numerous immune regulation/differentiation gene signatures enriched in RANKLhigh-expressing tumors”, say the two researchers.
Taken together, this study provides insight into the role of RANKL in immune tolerance and highlights the immunotherapeutic efficacy of its blockade in the context of triple-negative breast cancer.
Reference
RANKL blockade inhibits cancer growth through reversing the tolerogenic profile of tumor-infiltrating (plasmacytoid) dendritic cells.
J Immunother Cancer. 2025 Mar 13;13(3):e010753. doi: 10.1136/jitc-2024-010753.
