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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 5. Treg cells suppress osteoclast differentiation in vitro. (A–B) Treg cells suppressed osteoclast differentiation mediated by RANKL. Mouse bone marrow cells (BMCs) were cultured as described with RANKL in the absence or presence of Treg cells. The cultured cells were subject to TRAP staining. TRAP-positive multinucleated (> 3 nuclei) cells were counted. (A) Results are reported as the number of osteoclast (OC)-like cells per coverslip ± SD n = 5, *p < 0.01. (B) Representative images showed osteoclast (OC)-like cells. (C and D) Treg cells suppressed osteoclast differentiation mediated by M-CSF and CD8+ T cells. Mouse bone marrow cells were cultured as described with M-CSF (C) or activated CD8+ T cells (D) in the presence of different concentrations of Treg cells. Results are reported as the number of osteoclast (OC)-like cells per coverslip ± SD n = 6, *p < 0.01.
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Figure 5: Figure 5. Treg cells suppress osteoclast differentiation in vitro. (A–B) Treg cells suppressed osteoclast differentiation mediated by RANKL. Mouse bone marrow cells (BMCs) were cultured as described with RANKL in the absence or presence of Treg cells. The cultured cells were subject to TRAP staining. TRAP-positive multinucleated (> 3 nuclei) cells were counted. (A) Results are reported as the number of osteoclast (OC)-like cells per coverslip ± SD n = 5, *p < 0.01. (B) Representative images showed osteoclast (OC)-like cells. (C and D) Treg cells suppressed osteoclast differentiation mediated by M-CSF and CD8+ T cells. Mouse bone marrow cells were cultured as described with M-CSF (C) or activated CD8+ T cells (D) in the presence of different concentrations of Treg cells. Results are reported as the number of osteoclast (OC)-like cells per coverslip ± SD n = 6, *p < 0.01.

Mentions: In addition to immune suppression (Fig. 1), we hypothesized that high levels of Treg cells in the tumor associated bone marrow might affect bone pathology in prostate cancer. To test this, we sorted Treg cells and tested their potential roles in osteoclast differentiation induced by recombinant RANKL and M-CSF. As expected, Treg cells reduced the numbers of tartrate-resistant acid phosphatase (TRAP)-positive cells induced by RANKL (Fig. 5A and B) and M-CSF in a dose dependent manner (Fig. 5C). As activated CD8+ T cells were observed in bone marrow in patients with cancer,3-6 we further tested if Treg cells affected T cell-mediated osteoclast differentiation. We observed that TRAP+ cells were increased in CD8+ T cell coculture as compared with no T cells. Treg cells reduced the numbers of TRAP+ cells induced by CD8+ T cells in a dose dependent manner (Fig. 5D). The data indicates that Treg cells suppress osteoclast differentiation.


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 5. Treg cells suppress osteoclast differentiation in vitro. (A–B) Treg cells suppressed osteoclast differentiation mediated by RANKL. Mouse bone marrow cells (BMCs) were cultured as described with RANKL in the absence or presence of Treg cells. The cultured cells were subject to TRAP staining. TRAP-positive multinucleated (> 3 nuclei) cells were counted. (A) Results are reported as the number of osteoclast (OC)-like cells per coverslip ± SD n = 5, *p < 0.01. (B) Representative images showed osteoclast (OC)-like cells. (C and D) Treg cells suppressed osteoclast differentiation mediated by M-CSF and CD8+ T cells. Mouse bone marrow cells were cultured as described with M-CSF (C) or activated CD8+ T cells (D) in the presence of different concentrations of Treg cells. Results are reported as the number of osteoclast (OC)-like cells per coverslip ± SD n = 6, *p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3376984&req=5

Figure 5: Figure 5. Treg cells suppress osteoclast differentiation in vitro. (A–B) Treg cells suppressed osteoclast differentiation mediated by RANKL. Mouse bone marrow cells (BMCs) were cultured as described with RANKL in the absence or presence of Treg cells. The cultured cells were subject to TRAP staining. TRAP-positive multinucleated (> 3 nuclei) cells were counted. (A) Results are reported as the number of osteoclast (OC)-like cells per coverslip ± SD n = 5, *p < 0.01. (B) Representative images showed osteoclast (OC)-like cells. (C and D) Treg cells suppressed osteoclast differentiation mediated by M-CSF and CD8+ T cells. Mouse bone marrow cells were cultured as described with M-CSF (C) or activated CD8+ T cells (D) in the presence of different concentrations of Treg cells. Results are reported as the number of osteoclast (OC)-like cells per coverslip ± SD n = 6, *p < 0.01.
Mentions: In addition to immune suppression (Fig. 1), we hypothesized that high levels of Treg cells in the tumor associated bone marrow might affect bone pathology in prostate cancer. To test this, we sorted Treg cells and tested their potential roles in osteoclast differentiation induced by recombinant RANKL and M-CSF. As expected, Treg cells reduced the numbers of tartrate-resistant acid phosphatase (TRAP)-positive cells induced by RANKL (Fig. 5A and B) and M-CSF in a dose dependent manner (Fig. 5C). As activated CD8+ T cells were observed in bone marrow in patients with cancer,3-6 we further tested if Treg cells affected T cell-mediated osteoclast differentiation. We observed that TRAP+ cells were increased in CD8+ T cell coculture as compared with no T cells. Treg cells reduced the numbers of TRAP+ cells induced by CD8+ T cells in a dose dependent manner (Fig. 5D). The data indicates that Treg cells suppress osteoclast differentiation.

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