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Regulatory T cells in the bone marrow microenvironment in patients with prostate cancer.

Zhao E, Wang L, Dai J, Kryczek I, Wei S, Vatan L, Altuwaijri S, Sparwasser T, Wang G, Keller ET, Zou W - Oncoimmunology (2012)

Bottom Line: CD4(+)CD25(+) regulatory T (Treg) cells contribute to self-tolerance and tumor immune pathology.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.In vivo Treg cell depletion results in reduced bone density in tumor bearing mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery; University of Michigan; Ann Arbor, MI USA ; Department of Surgery; Central Laboratory; Union Hospital; Tongji Medical College; Huazhong University of Science and Technology; Wuhan, China.

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.

No MeSH data available.


Related in: MedlinePlus

Figure 6. Treg cells suppress osteoclast differentiation and function in vivo. (A–C) Human Treg cells suppressed osteoclast differentiation. Prostate cancer bone metastasis was established in NOD.SCID mice with PC-3 intratibial injection. On day 7 after tumor inoculation, mice were intravenously transfused with activated Treg cells. On day 25, BMD (A) and BMC (B) of tibial trabeculae were measured. Representative radiographic images showed the bone destruction of tibial trabeculae (C) on day 25. Results are expressed as mean ± SD n = 6/group, *p < 0.05. (D and E) Mouse Treg cells suppressed osteoclast differentiation. RM1 tumor bone metastasis was established in DEREG mice with tumor intratibial injection. Treg cells were depleted with DT injection. On day 15, BMD (D) and BMC (E) of tibial trabeculae were measured. Results are expressed as mean ± SD n = 5/group, *p < 0.05. DT, diphtheria toxin.
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Figure 6: Figure 6. Treg cells suppress osteoclast differentiation and function in vivo. (A–C) Human Treg cells suppressed osteoclast differentiation. Prostate cancer bone metastasis was established in NOD.SCID mice with PC-3 intratibial injection. On day 7 after tumor inoculation, mice were intravenously transfused with activated Treg cells. On day 25, BMD (A) and BMC (B) of tibial trabeculae were measured. Representative radiographic images showed the bone destruction of tibial trabeculae (C) on day 25. Results are expressed as mean ± SD n = 6/group, *p < 0.05. (D and E) Mouse Treg cells suppressed osteoclast differentiation. RM1 tumor bone metastasis was established in DEREG mice with tumor intratibial injection. Treg cells were depleted with DT injection. On day 15, BMD (D) and BMC (E) of tibial trabeculae were measured. Results are expressed as mean ± SD n = 5/group, *p < 0.05. DT, diphtheria toxin.

Mentions: We tested the effects of Treg cells in vivo on bone pathology in our established human prostate cancer chimeric model. Human prostate cancer cells PC-3 were inoculated into tibia of NOD.SCID mice by intratibial injection.16-20 Tumor bone establishment was examined with both in vivo bioluminescence and radiographic imaging. Activated Treg cells were transfused into the mice by intravenous injection seven days after the establishment of bone metastasis. We showed that Treg cells increased bone mineral density (BMD) (Fig. 6A), bone mineral content (BMC) (Fig. 6B) and ameliorated bone destruction of tibial trabeculae (Fig. 6C) compared with control.


Regulatory T cells in the bone marrow microenvironment in patients with prostate cancer.

Zhao E, Wang L, Dai J, Kryczek I, Wei S, Vatan L, Altuwaijri S, Sparwasser T, Wang G, Keller ET, Zou W - Oncoimmunology (2012)

Figure 6. Treg cells suppress osteoclast differentiation and function in vivo. (A–C) Human Treg cells suppressed osteoclast differentiation. Prostate cancer bone metastasis was established in NOD.SCID mice with PC-3 intratibial injection. On day 7 after tumor inoculation, mice were intravenously transfused with activated Treg cells. On day 25, BMD (A) and BMC (B) of tibial trabeculae were measured. Representative radiographic images showed the bone destruction of tibial trabeculae (C) on day 25. Results are expressed as mean ± SD n = 6/group, *p < 0.05. (D and E) Mouse Treg cells suppressed osteoclast differentiation. RM1 tumor bone metastasis was established in DEREG mice with tumor intratibial injection. Treg cells were depleted with DT injection. On day 15, BMD (D) and BMC (E) of tibial trabeculae were measured. Results are expressed as mean ± SD n = 5/group, *p < 0.05. DT, diphtheria toxin.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 6: Figure 6. Treg cells suppress osteoclast differentiation and function in vivo. (A–C) Human Treg cells suppressed osteoclast differentiation. Prostate cancer bone metastasis was established in NOD.SCID mice with PC-3 intratibial injection. On day 7 after tumor inoculation, mice were intravenously transfused with activated Treg cells. On day 25, BMD (A) and BMC (B) of tibial trabeculae were measured. Representative radiographic images showed the bone destruction of tibial trabeculae (C) on day 25. Results are expressed as mean ± SD n = 6/group, *p < 0.05. (D and E) Mouse Treg cells suppressed osteoclast differentiation. RM1 tumor bone metastasis was established in DEREG mice with tumor intratibial injection. Treg cells were depleted with DT injection. On day 15, BMD (D) and BMC (E) of tibial trabeculae were measured. Results are expressed as mean ± SD n = 5/group, *p < 0.05. DT, diphtheria toxin.
Mentions: We tested the effects of Treg cells in vivo on bone pathology in our established human prostate cancer chimeric model. Human prostate cancer cells PC-3 were inoculated into tibia of NOD.SCID mice by intratibial injection.16-20 Tumor bone establishment was examined with both in vivo bioluminescence and radiographic imaging. Activated Treg cells were transfused into the mice by intravenous injection seven days after the establishment of bone metastasis. We showed that Treg cells increased bone mineral density (BMD) (Fig. 6A), bone mineral content (BMC) (Fig. 6B) and ameliorated bone destruction of tibial trabeculae (Fig. 6C) compared with control.

Bottom Line: CD4(+)CD25(+) regulatory T (Treg) cells contribute to self-tolerance and tumor immune pathology.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.In vivo Treg cell depletion results in reduced bone density in tumor bearing mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery; University of Michigan; Ann Arbor, MI USA ; Department of Surgery; Central Laboratory; Union Hospital; Tongji Medical College; Huazhong University of Science and Technology; Wuhan, China.

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.

No MeSH data available.


Related in: MedlinePlus