Myeloid cell reprogramming combined with zoledronic acid effectively suppresses bone metastasis

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Bone metastases are challenging to treat due to an immunosuppressive tumor microenvironment (TME) dominated by myeloid cells.
• The specific roles and regulatory mechanisms of myeloid cells in the bone TME remain unclear.
• Understanding these mechanisms is crucial for developing effective therapies.

Purpose of the Study:

• To investigate the role of the DKK1-CKAP4 axis in myeloid cell-mediated immunosuppression within bone metastases.
• To identify potential therapeutic strategies targeting the DKK1-CKAP4 pathway for bone metastasis treatment.

Main Methods:

• Analysis of myeloid cell composition and phenotype in the bone TME.
• Ex vivo co-culture systems and an in vivo neutrophil-specific Ckap4 knockout mouse model were used.
• Evaluation of DKK1 blockade combined with zoledronic acid in bone metastasis mouse models.

Main Results:

• The DKK1-CKAP4 axis was found to regulate multiple myeloid populations, promoting immunosuppressive neutrophil phenotypes, osteoclast differentiation, and M2-like macrophage polarization.
• Combined DKK1 blockade and zoledronic acid therapy reprogrammed immunosuppressive myeloid cells.
• This combination therapy restored antitumor immunity and significantly reduced tumor burden in bone metastasis models.

Conclusions:

• The DKK1-CKAP4 axis is a critical regulator of myeloid-driven immunosuppression in the bone TME.
• Combination therapy with DKK1 blockade and zoledronic acid presents a promising therapeutic strategy for managing bone metastases.