1. Regulatory T cells in the bone marrow microenvironment in patients with prostate cancer
- Author
-
Jinlu Dai, Weiping Zou, Ilona Kryczek, Guobin Wang, Shuang Wei, Ende Zhao, Evan T. Keller, Tim Sparwasser, Saleh Altuwaijri, Linda Vatan, and Lin Wang
- Subjects
regulatory T cell ,Stromal cell ,bone marrow ,Regulatory T cell ,dendritic cell ,Immunology ,chemical and pharmacologic phenomena ,RANK ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Osteoclast ,Immunology and Allergy ,Medicine ,030304 developmental biology ,Bone mineral ,CXCR4 ,0303 health sciences ,business.industry ,RANKL ,Bone metastasis ,hemic and immune systems ,Dendritic cell ,CXCL12 ,medicine.disease ,prostate cancer ,3. Good health ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Bone marrow ,business ,Research Paper - Abstract
Human prostate cancer frequently metastasizes to bone marrow. What defines the cellular and molecular predilection for prostate cancer to metastasize to bone marrow is not well understood. CD4(+)CD25(+) regulatory T (Treg) cells contribute to self-tolerance and tumor immune pathology. We now show that functional Treg cells are increased in the bone marrow microenvironment in prostate cancer patients with bone metastasis, and that CXCR4/CXCL12 signaling pathway contributes to Treg cell bone marrow trafficking. Treg cells exhibit active cell cycling in the bone marrow, and bone marrow dendritic cells express high levels of receptor activator of NFκB (RANK), and promote Treg cell expansion through RANK and its ligand (RANKL) signals. Furthermore, Treg cells suppress osteoclast differentiation induced by activated T cells and M-CSF, adoptive transferred Treg cells migrate to bone marrow, and increase bone mineral intensity in the xenograft mouse models with human prostate cancer bone marrow inoculation. In vivo Treg cell depletion results in reduced bone density in tumor bearing mice. The data indicates that bone marrow Treg cells may form an immunosuppressive niche to facilitate cancer bone metastasis and contribute to bone deposition, the major bone pathology in prostate cancer patients with bone metastasis. These findings mechanistically explain why Treg cells accumulate in the bone marrow, and demonstrate a previously unappreciated role for Treg cells in patients with prostate cancer. Thus, targeting Treg cells may not only improve anti-tumor immunity, but also ameliorate bone pathology in prostate cancer patients with bone metastasis.
- Published
- 2012