To characterize the microenvironment of bone metastatic prostate cancer (PCa), Kfoury et al. analyzed single cells from distinct vertebral regions encompassing metastatic tumors, involved and uninvolved bone marrow, and cancer free-controls. Metastatic PCa was associated with an immune-suppressive environment with increased numbers of exhausted and dysfunctional T cells, and increased inflammatory monocytes and immunosuppressive M2 macrophages, which expressed high levels of CCL20. In a bone metastatic PCa mouse model, inhibition of CCR6 signaling significantly improved survival, increased IFNγ production, and restored CTL function.
Contributed by Katherine Turner
ABSTRACT: 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.
Author Info: (1) Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Bio
Author Info: (1) Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. (2) Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Childhood Cancer Research Unit, Department of Women's Health and Children's, Karolinska Institutet, Stockholm, Sweden. Electronic address: n.baryawno@ki.se. (3) Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. (4) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. (5) Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. (6) Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. (7) Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. (8) Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. (9) St. Petersburg Polytechnical University, St. Petersburg, Russia. (10) Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. (11) Department of Neurosurgery, Harvard Medical School, Boston, MA, USA. (12) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. (13) Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Boston, MA, USA. (14) Department of Neurosurgery, Harvard Medical School, Boston, MA, USA. (15) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA. (16) Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. (17) Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. (18) Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. Electronic address: peter_kharchenko@hms.harvard.edu.
