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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 1. High levels of functional Treg cells in prostate cancer associated bone marrow. (A and B) High levels of CD4+Foxp3+ cells in bone marrow. Bone marrow and blood single cell suspensions were made from normal age-matched male donors (n = 8) and patients with prostate cancer (PC) (n = 6). The cells were subject to staining with anti-CD3, anti-CD4 and anti-FOXP3. Cells were analyzed with multiple color staining. The histogram showed the percentage of FOXP3+ cells in CD3+CD4+ (A). One of 6–8 donors is shown. Results are expressed as the mean values ± SD (B) *p < 0.01. PC, prostate cancer. (C–E) Bone marrow Treg cells are functional. CD3+CD4+CD25high cells were sorted with FACSAria, to high purity (> 97%), from bone marrow in patients with prostate cancer. Autologous CD3+CD25- blood T cells (5 × 104/ml) were stimulated with anti-CD3 (5 μg/ml) for 3 d with or without different numbers of Treg cells. T cell proliferation was detected by [3H] thymidine incorporation (C) and the production of interferon-γ (D) and IL-2 (E) were detected by ELISA. (n = 5; *p < 0.01). Three patients in Gleason grade 4 and 3 in grade 5, and 2 patients in stage T3a, 2 in T3b and 2 in M1.
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Figure 1: Figure 1. High levels of functional Treg cells in prostate cancer associated bone marrow. (A and B) High levels of CD4+Foxp3+ cells in bone marrow. Bone marrow and blood single cell suspensions were made from normal age-matched male donors (n = 8) and patients with prostate cancer (PC) (n = 6). The cells were subject to staining with anti-CD3, anti-CD4 and anti-FOXP3. Cells were analyzed with multiple color staining. The histogram showed the percentage of FOXP3+ cells in CD3+CD4+ (A). One of 6–8 donors is shown. Results are expressed as the mean values ± SD (B) *p < 0.01. PC, prostate cancer. (C–E) Bone marrow Treg cells are functional. CD3+CD4+CD25high cells were sorted with FACSAria, to high purity (> 97%), from bone marrow in patients with prostate cancer. Autologous CD3+CD25- blood T cells (5 × 104/ml) were stimulated with anti-CD3 (5 μg/ml) for 3 d with or without different numbers of Treg cells. T cell proliferation was detected by [3H] thymidine incorporation (C) and the production of interferon-γ (D) and IL-2 (E) were detected by ELISA. (n = 5; *p < 0.01). Three patients in Gleason grade 4 and 3 in grade 5, and 2 patients in stage T3a, 2 in T3b and 2 in M1.

Mentions: Prostate cancer frequently metastasizes to bone marrow. Recent reports suggest that bone marrow is a site for important T cell events.6,7,11 We previously observed high levels of Treg cells in normal bone marrow.9 We now examined the Treg compartment in patients with prostate cancer. We first showed that the fraction of Treg cells in CD4+ T cells was significantly higher in bone marrow in patients with prostate cancer without bone metastasis than that in normal blood and blood from patients with prostate cancer (n = 8, p < 0.01 for each). Interestingly, the levels of Treg cells were significantly higher in bone marrow from patients with prostate cancer bone marrow metastasis (37 ± 11%, n = 6, p < 0.001) than that in the bone marrow in prostate cancer patients without bone marrow metastasis (18 ± 8%, n = 6) (Fig. 1A and B). Thus, high levels of Treg cells are found in prostate cancer bone marrow metastasis.


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 1. High levels of functional Treg cells in prostate cancer associated bone marrow. (A and B) High levels of CD4+Foxp3+ cells in bone marrow. Bone marrow and blood single cell suspensions were made from normal age-matched male donors (n = 8) and patients with prostate cancer (PC) (n = 6). The cells were subject to staining with anti-CD3, anti-CD4 and anti-FOXP3. Cells were analyzed with multiple color staining. The histogram showed the percentage of FOXP3+ cells in CD3+CD4+ (A). One of 6–8 donors is shown. Results are expressed as the mean values ± SD (B) *p < 0.01. PC, prostate cancer. (C–E) Bone marrow Treg cells are functional. CD3+CD4+CD25high cells were sorted with FACSAria, to high purity (> 97%), from bone marrow in patients with prostate cancer. Autologous CD3+CD25- blood T cells (5 × 104/ml) were stimulated with anti-CD3 (5 μg/ml) for 3 d with or without different numbers of Treg cells. T cell proliferation was detected by [3H] thymidine incorporation (C) and the production of interferon-γ (D) and IL-2 (E) were detected by ELISA. (n = 5; *p < 0.01). Three patients in Gleason grade 4 and 3 in grade 5, and 2 patients in stage T3a, 2 in T3b and 2 in M1.
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Figure 1: Figure 1. High levels of functional Treg cells in prostate cancer associated bone marrow. (A and B) High levels of CD4+Foxp3+ cells in bone marrow. Bone marrow and blood single cell suspensions were made from normal age-matched male donors (n = 8) and patients with prostate cancer (PC) (n = 6). The cells were subject to staining with anti-CD3, anti-CD4 and anti-FOXP3. Cells were analyzed with multiple color staining. The histogram showed the percentage of FOXP3+ cells in CD3+CD4+ (A). One of 6–8 donors is shown. Results are expressed as the mean values ± SD (B) *p < 0.01. PC, prostate cancer. (C–E) Bone marrow Treg cells are functional. CD3+CD4+CD25high cells were sorted with FACSAria, to high purity (> 97%), from bone marrow in patients with prostate cancer. Autologous CD3+CD25- blood T cells (5 × 104/ml) were stimulated with anti-CD3 (5 μg/ml) for 3 d with or without different numbers of Treg cells. T cell proliferation was detected by [3H] thymidine incorporation (C) and the production of interferon-γ (D) and IL-2 (E) were detected by ELISA. (n = 5; *p < 0.01). Three patients in Gleason grade 4 and 3 in grade 5, and 2 patients in stage T3a, 2 in T3b and 2 in M1.
Mentions: Prostate cancer frequently metastasizes to bone marrow. Recent reports suggest that bone marrow is a site for important T cell events.6,7,11 We previously observed high levels of Treg cells in normal bone marrow.9 We now examined the Treg compartment in patients with prostate cancer. We first showed that the fraction of Treg cells in CD4+ T cells was significantly higher in bone marrow in patients with prostate cancer without bone metastasis than that in normal blood and blood from patients with prostate cancer (n = 8, p < 0.01 for each). Interestingly, the levels of Treg cells were significantly higher in bone marrow from patients with prostate cancer bone marrow metastasis (37 ± 11%, n = 6, p < 0.001) than that in the bone marrow in prostate cancer patients without bone marrow metastasis (18 ± 8%, n = 6) (Fig. 1A and B). Thus, high levels of Treg cells are found in prostate cancer bone marrow metastasis.

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