Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment

Bone metastases are devastating complications of cancer. They are particularly common in prostate cancer (PCa), represent incurable disease, and are refractory to immunotherapy. We seek to define distinct features of the bone marrow (BM) microenvironment by analyzing single cells from bone metastatic prostate tumors, involved BM, uninvolved BM, and BM from cancer-free, orthopedic patients, and healthy individuals. Metastatic PCa is associated with multifaceted immune distortion, specifically exhaustion of distinct T cell subsets, appearance of macrophages with states specific to PCa bone metastases. The chemokine CCL20 is notably overexpressed by myeloid cells, as is its cognate CCR6 receptor on T cells. Disruption of the CCL20-CCR6 axis in mice with syngeneic PCa bone metastases restores T cell reactivity and significantly prolongs animal survival. Comparative high-resolution analysis of PCa bone metastases shows a targeted approach for relieving local immunosuppression for therapeutic effect.

Automated summary

Bone metastases are devastating complications of cancer, particularly common in prostate cancer and refractory to immunotherapy. Analysis of single cells reveals multifaceted immune distortion in metastatic prostate cancer, with overexpression of CCL20 by myeloid cells and appearance of unique macrophages specific to PCa bone metastases. Disruption of the CCL20-CCR6 axis restores T cell reactivity and prolongs animal survival in mice with syngeneic PCa bone metastases, suggesting a targeted approach for relieving local immunosuppression.