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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 4. RANK+ DCs induce Treg cell expansion in tumor associated bone marrow. (A) Prostate cancer associated bone marrow DCs stimulated Treg cell expansion. Bone marrow lin-CD11c+ DCs were sorted from human bone marrow, and cultured with blood Treg cells for 4 d as described. The resultant cells were stained with anti-Foxp3. Results are expressed the absolute numbers of Treg cells ± SD n = 5, p < 0.01. (B) Prostate cancer BM DCs expressed RANK. BM cells were stained for DC phenotype and RANK. Results are expressed the percent of RANK+ cells in lin-CD11c+ DCs. One of 5 is shown. (C) Prostate cancer BM DCs mediated Treg cell expansion through RANK. RANK+ and RANK- DCs were sorted and cultured with Treg cells as described (A) in the absence or presence of OPG. Cells were collected for detecting Foxp3 with LSR by gating on CD3+CD4+ viable cells. Results are expressed as the absolute numbers of Foxp3+ cells ± SD n = 5, *p < 0.01.
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Figure 4: Figure 4. RANK+ DCs induce Treg cell expansion in tumor associated bone marrow. (A) Prostate cancer associated bone marrow DCs stimulated Treg cell expansion. Bone marrow lin-CD11c+ DCs were sorted from human bone marrow, and cultured with blood Treg cells for 4 d as described. The resultant cells were stained with anti-Foxp3. Results are expressed the absolute numbers of Treg cells ± SD n = 5, p < 0.01. (B) Prostate cancer BM DCs expressed RANK. BM cells were stained for DC phenotype and RANK. Results are expressed the percent of RANK+ cells in lin-CD11c+ DCs. One of 5 is shown. (C) Prostate cancer BM DCs mediated Treg cell expansion through RANK. RANK+ and RANK- DCs were sorted and cultured with Treg cells as described (A) in the absence or presence of OPG. Cells were collected for detecting Foxp3 with LSR by gating on CD3+CD4+ viable cells. Results are expressed as the absolute numbers of Foxp3+ cells ± SD n = 5, *p < 0.01.

Mentions: We further investigated the cellular mechanism by which Treg cells were expanding in the tumor associated bone marrow. We hypothesized that tumor associated DCs might induce Treg cells expansion. We sorted blood Treg cells and cocultured with DCs from different sources. We showed that regardless of their source, DCs efficiently induced Treg cell expansion. However, tumor associated bone marrow DCs were superior to inducing Treg cell expansion as compared with DCs from normal bone marrow and blood (Fig. 4A). Interestingly, tumor bone marrow-associated DCs highly expressed RANK. DCs from normal blood or bone marrow without tumor in the bone marrow expressed little RANK (Fig. 4B). These DCs expressed similar levels of CD40 (Fig. 4B). To study the effects of RANK+ DCs on Treg cell expansion, we sorted RANK+ and RANK- DCs from tumor associated bone marrow, and cultured with Treg cells. We observed that RANK+ and RANK- DCs induced Treg cell expansion, however, RANK+ DCs were more efficient than RANK- DCs to induce Treg cell expansion (Fig. 4C). Furthermore, blocking RANK/RANKL signaling pathway with recombinant osteoprotegerin (OPG) ablated the stimulatory effects of RANK+ DCs on Treg cell expansion (Fig. 4C). These observations suggest that RANK+ DCs may be responsible for Treg cell expansion in patients with prostate cancer.


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 4. RANK+ DCs induce Treg cell expansion in tumor associated bone marrow. (A) Prostate cancer associated bone marrow DCs stimulated Treg cell expansion. Bone marrow lin-CD11c+ DCs were sorted from human bone marrow, and cultured with blood Treg cells for 4 d as described. The resultant cells were stained with anti-Foxp3. Results are expressed the absolute numbers of Treg cells ± SD n = 5, p < 0.01. (B) Prostate cancer BM DCs expressed RANK. BM cells were stained for DC phenotype and RANK. Results are expressed the percent of RANK+ cells in lin-CD11c+ DCs. One of 5 is shown. (C) Prostate cancer BM DCs mediated Treg cell expansion through RANK. RANK+ and RANK- DCs were sorted and cultured with Treg cells as described (A) in the absence or presence of OPG. Cells were collected for detecting Foxp3 with LSR by gating on CD3+CD4+ viable cells. Results are expressed as the absolute numbers of Foxp3+ cells ± SD n = 5, *p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 4: Figure 4. RANK+ DCs induce Treg cell expansion in tumor associated bone marrow. (A) Prostate cancer associated bone marrow DCs stimulated Treg cell expansion. Bone marrow lin-CD11c+ DCs were sorted from human bone marrow, and cultured with blood Treg cells for 4 d as described. The resultant cells were stained with anti-Foxp3. Results are expressed the absolute numbers of Treg cells ± SD n = 5, p < 0.01. (B) Prostate cancer BM DCs expressed RANK. BM cells were stained for DC phenotype and RANK. Results are expressed the percent of RANK+ cells in lin-CD11c+ DCs. One of 5 is shown. (C) Prostate cancer BM DCs mediated Treg cell expansion through RANK. RANK+ and RANK- DCs were sorted and cultured with Treg cells as described (A) in the absence or presence of OPG. Cells were collected for detecting Foxp3 with LSR by gating on CD3+CD4+ viable cells. Results are expressed as the absolute numbers of Foxp3+ cells ± SD n = 5, *p < 0.01.
Mentions: We further investigated the cellular mechanism by which Treg cells were expanding in the tumor associated bone marrow. We hypothesized that tumor associated DCs might induce Treg cells expansion. We sorted blood Treg cells and cocultured with DCs from different sources. We showed that regardless of their source, DCs efficiently induced Treg cell expansion. However, tumor associated bone marrow DCs were superior to inducing Treg cell expansion as compared with DCs from normal bone marrow and blood (Fig. 4A). Interestingly, tumor bone marrow-associated DCs highly expressed RANK. DCs from normal blood or bone marrow without tumor in the bone marrow expressed little RANK (Fig. 4B). These DCs expressed similar levels of CD40 (Fig. 4B). To study the effects of RANK+ DCs on Treg cell expansion, we sorted RANK+ and RANK- DCs from tumor associated bone marrow, and cultured with Treg cells. We observed that RANK+ and RANK- DCs induced Treg cell expansion, however, RANK+ DCs were more efficient than RANK- DCs to induce Treg cell expansion (Fig. 4C). Furthermore, blocking RANK/RANKL signaling pathway with recombinant osteoprotegerin (OPG) ablated the stimulatory effects of RANK+ DCs on Treg cell expansion (Fig. 4C). These observations suggest that RANK+ DCs may be responsible for Treg cell expansion in patients with prostate cancer.

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