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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 3. Treg cells actively expand in tumor associated bone marrow. Blood and bone marrow were immediately stained with anti-CD3, anti-CD4, anti-FOXP3 and anti-Ki67 and were analyzed with LSR II. (A) Representative dot plots showed Ki67 expression in normal vs. tumor bone marrow Foxp3+ Treg cells. (B) Results are expressed as the percentage of Ki67 expressing cells in CD4+FOXP3+CD3+ cells (Treg cells) (mean ± SEM) (n = 6–8, *, Tumor bone marrow compared with normal bone marrow, and other compartments, p < 0.001). (C and D) Bone marrow Treg cells expressed different levels of cell cycling genes. Expression of multiple cyclin genes (C) and CDK inhibitors (D) was quantified in bone Treg cells and conventional T cells by real-time PCR. Results are expressed as mean ± SD n = 5, *p < 0.01.
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Figure 3: Figure 3. Treg cells actively expand in tumor associated bone marrow. Blood and bone marrow were immediately stained with anti-CD3, anti-CD4, anti-FOXP3 and anti-Ki67 and were analyzed with LSR II. (A) Representative dot plots showed Ki67 expression in normal vs. tumor bone marrow Foxp3+ Treg cells. (B) Results are expressed as the percentage of Ki67 expressing cells in CD4+FOXP3+CD3+ cells (Treg cells) (mean ± SEM) (n = 6–8, *, Tumor bone marrow compared with normal bone marrow, and other compartments, p < 0.001). (C and D) Bone marrow Treg cells expressed different levels of cell cycling genes. Expression of multiple cyclin genes (C) and CDK inhibitors (D) was quantified in bone Treg cells and conventional T cells by real-time PCR. Results are expressed as mean ± SD n = 5, *p < 0.01.

Mentions: After examining the possibility of Treg cell bone marrow trafficking, we further analyzed whether Treg cells were actively expanded in the tumor associated bone marrow in patients with prostate cancer. We showed that normal bone marrow Treg cells contained up to 7% Ki67 expressing cells whereas there were 1% Ki67+ Treg cells in peripheral blood. Interestingly, there were 32% Ki67+ bone marrow Treg cells in patients with prostate cancers (Fig. 3A and B). In accord with this, the expression of multiple cyclin genes was higher in bone marrow Treg cells than conventional T cells (Fig. 3C). On the contrary, the expression of multiple CDK inhibitors was lower in bone marrow Treg cells than conventional T cells (Fig. 3D). The data suggests that Treg cells in the tumor associated bone marrow selectively experience a pathological expansion.


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 3. Treg cells actively expand in tumor associated bone marrow. Blood and bone marrow were immediately stained with anti-CD3, anti-CD4, anti-FOXP3 and anti-Ki67 and were analyzed with LSR II. (A) Representative dot plots showed Ki67 expression in normal vs. tumor bone marrow Foxp3+ Treg cells. (B) Results are expressed as the percentage of Ki67 expressing cells in CD4+FOXP3+CD3+ cells (Treg cells) (mean ± SEM) (n = 6–8, *, Tumor bone marrow compared with normal bone marrow, and other compartments, p < 0.001). (C and D) Bone marrow Treg cells expressed different levels of cell cycling genes. Expression of multiple cyclin genes (C) and CDK inhibitors (D) was quantified in bone Treg cells and conventional T cells by real-time PCR. Results are expressed as mean ± SD n = 5, *p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Figure 3. Treg cells actively expand in tumor associated bone marrow. Blood and bone marrow were immediately stained with anti-CD3, anti-CD4, anti-FOXP3 and anti-Ki67 and were analyzed with LSR II. (A) Representative dot plots showed Ki67 expression in normal vs. tumor bone marrow Foxp3+ Treg cells. (B) Results are expressed as the percentage of Ki67 expressing cells in CD4+FOXP3+CD3+ cells (Treg cells) (mean ± SEM) (n = 6–8, *, Tumor bone marrow compared with normal bone marrow, and other compartments, p < 0.001). (C and D) Bone marrow Treg cells expressed different levels of cell cycling genes. Expression of multiple cyclin genes (C) and CDK inhibitors (D) was quantified in bone Treg cells and conventional T cells by real-time PCR. Results are expressed as mean ± SD n = 5, *p < 0.01.
Mentions: After examining the possibility of Treg cell bone marrow trafficking, we further analyzed whether Treg cells were actively expanded in the tumor associated bone marrow in patients with prostate cancer. We showed that normal bone marrow Treg cells contained up to 7% Ki67 expressing cells whereas there were 1% Ki67+ Treg cells in peripheral blood. Interestingly, there were 32% Ki67+ bone marrow Treg cells in patients with prostate cancers (Fig. 3A and B). In accord with this, the expression of multiple cyclin genes was higher in bone marrow Treg cells than conventional T cells (Fig. 3C). On the contrary, the expression of multiple CDK inhibitors was lower in bone marrow Treg cells than conventional T cells (Fig. 3D). The data suggests that Treg cells in the tumor associated bone marrow selectively experience a pathological expansion.

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