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FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy.

Ghebeh H, Barhoush E, Tulbah A, Elkum N, Al-Tweigeri T, Dermime S - BMC Cancer (2008)

Bottom Line: B7-H1 is an inhibitory molecule that binds to PD-1 on T lymphocytes, while FOXP3 is a marker for regulatory T cells (Tregs).A co-existence of B7-H1+ T lymphocytes and FOXP3+ Tregs was evidenced by the highly significant correlation of these molecules (P < .0001) and their expression by different T lymphocyte subsets was clearly demonstrated.Interestingly, concomitant presence of FOXP3+ Tregs, B7-H1+ and PD-1+ TIL synergistically correlated with high histological grade (III) (P < .001), estrogen receptor negative status (P = .017), and the presence of severe lymphocytic infiltration (P = .022).

View Article: PubMed Central - HTML - PubMed

Affiliation: Tumor Immunology Section, King Faisal Specialist Hospital and Research Center, P,O, Box 3354, Riyadh 11211, Saudi Arabia. hghebeh@kfshrc.edu.sa

ABSTRACT

Background: Recent studies have demonstrated a direct involvement of B7-H1, PD-1 and FOXP3 molecules in the immune escape of cancer. B7-H1 is an inhibitory molecule that binds to PD-1 on T lymphocytes, while FOXP3 is a marker for regulatory T cells (Tregs). We have previously demonstrated the association of B7-H1-expressing T infiltrating lymphocytes (TIL) with high-risk breast cancer patients while other studies reported the involvement of FOXP3+ Tregs as a bad prognostic factor in breast tumors. Although the co-existence between the two types of cells has been demonstrated in vitro and animal models, their relative infiltration and correlation with the clinicopathological parameters of cancer patients have not been well studied. Therefore, we investigated TIL-expressing the B7-H1, PD-1, and FOXP3 molecules, in the microenvironment of human breast tumors and their possible association with the progression of the disease.

Methods: Using immunohistochemistry, tumor sections from 62 breast cancer patients were co-stained for B7-H1, PD-1 and FOXP3 molecules and their expression was statistically correlated with factors known to be involved in the progression of the disease.

Results: A co-existence of B7-H1+ T lymphocytes and FOXP3+ Tregs was evidenced by the highly significant correlation of these molecules (P < .0001) and their expression by different T lymphocyte subsets was clearly demonstrated. Interestingly, concomitant presence of FOXP3+ Tregs, B7-H1+ and PD-1+ TIL synergistically correlated with high histological grade (III) (P < .001), estrogen receptor negative status (P = .017), and the presence of severe lymphocytic infiltration (P = .022).

Conclusion: Accumulation of TIL-expressing such inhibitory molecules may deteriorate the immunity of high-risk breast cancer patients and this should encourage vigorous combinatorial immunotherapeutic approaches targeting Tregs and B7-H1/PD-1 molecules.

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Related in: MedlinePlus

Immunohistochemical staining showing intratumoral and intrastromal FOXP3+ Tregs in breast cancer tissues. Representative micrographs at × 530 magnification of CD3+ (red color membranous expression) and FOXP3+ (brown color nuclear expression) TIL of (A) intrastromal (left) and intratumoral (right) sections. Solid arrow indicates a CD3+/FOXP3+ Treg cell and dashed arrow indicates a CD3+/FOXP3- cell. (B) Intratumoral FOXP3+ TIL with different staining intensity (Intense, Medium, and weak). Cells were counterstained with hematoxylin.
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Figure 2: Immunohistochemical staining showing intratumoral and intrastromal FOXP3+ Tregs in breast cancer tissues. Representative micrographs at × 530 magnification of CD3+ (red color membranous expression) and FOXP3+ (brown color nuclear expression) TIL of (A) intrastromal (left) and intratumoral (right) sections. Solid arrow indicates a CD3+/FOXP3+ Treg cell and dashed arrow indicates a CD3+/FOXP3- cell. (B) Intratumoral FOXP3+ TIL with different staining intensity (Intense, Medium, and weak). Cells were counterstained with hematoxylin.

Mentions: Both intratumoral and intrastromal FOXP3+CD3+ cells were present in the patients tissues (Figure 2A) and the expression level of FOXP3 in the intratumoral Tregs ranged from weak to intense (Figure 2B). Interestingly, most of FOXP3 intensely stained Tregs were found in close proximity to tumor cells. PD-1+ T lymphocytes were found both intrastromal and intratumoral, where they commonly seen in clumps, or as clumps/single cells respectively.


FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy.

Ghebeh H, Barhoush E, Tulbah A, Elkum N, Al-Tweigeri T, Dermime S - BMC Cancer (2008)

Immunohistochemical staining showing intratumoral and intrastromal FOXP3+ Tregs in breast cancer tissues. Representative micrographs at × 530 magnification of CD3+ (red color membranous expression) and FOXP3+ (brown color nuclear expression) TIL of (A) intrastromal (left) and intratumoral (right) sections. Solid arrow indicates a CD3+/FOXP3+ Treg cell and dashed arrow indicates a CD3+/FOXP3- cell. (B) Intratumoral FOXP3+ TIL with different staining intensity (Intense, Medium, and weak). Cells were counterstained with hematoxylin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2279136&req=5

Figure 2: Immunohistochemical staining showing intratumoral and intrastromal FOXP3+ Tregs in breast cancer tissues. Representative micrographs at × 530 magnification of CD3+ (red color membranous expression) and FOXP3+ (brown color nuclear expression) TIL of (A) intrastromal (left) and intratumoral (right) sections. Solid arrow indicates a CD3+/FOXP3+ Treg cell and dashed arrow indicates a CD3+/FOXP3- cell. (B) Intratumoral FOXP3+ TIL with different staining intensity (Intense, Medium, and weak). Cells were counterstained with hematoxylin.
Mentions: Both intratumoral and intrastromal FOXP3+CD3+ cells were present in the patients tissues (Figure 2A) and the expression level of FOXP3 in the intratumoral Tregs ranged from weak to intense (Figure 2B). Interestingly, most of FOXP3 intensely stained Tregs were found in close proximity to tumor cells. PD-1+ T lymphocytes were found both intrastromal and intratumoral, where they commonly seen in clumps, or as clumps/single cells respectively.

Bottom Line: B7-H1 is an inhibitory molecule that binds to PD-1 on T lymphocytes, while FOXP3 is a marker for regulatory T cells (Tregs).A co-existence of B7-H1+ T lymphocytes and FOXP3+ Tregs was evidenced by the highly significant correlation of these molecules (P < .0001) and their expression by different T lymphocyte subsets was clearly demonstrated.Interestingly, concomitant presence of FOXP3+ Tregs, B7-H1+ and PD-1+ TIL synergistically correlated with high histological grade (III) (P < .001), estrogen receptor negative status (P = .017), and the presence of severe lymphocytic infiltration (P = .022).

View Article: PubMed Central - HTML - PubMed

Affiliation: Tumor Immunology Section, King Faisal Specialist Hospital and Research Center, P,O, Box 3354, Riyadh 11211, Saudi Arabia. hghebeh@kfshrc.edu.sa

ABSTRACT

Background: Recent studies have demonstrated a direct involvement of B7-H1, PD-1 and FOXP3 molecules in the immune escape of cancer. B7-H1 is an inhibitory molecule that binds to PD-1 on T lymphocytes, while FOXP3 is a marker for regulatory T cells (Tregs). We have previously demonstrated the association of B7-H1-expressing T infiltrating lymphocytes (TIL) with high-risk breast cancer patients while other studies reported the involvement of FOXP3+ Tregs as a bad prognostic factor in breast tumors. Although the co-existence between the two types of cells has been demonstrated in vitro and animal models, their relative infiltration and correlation with the clinicopathological parameters of cancer patients have not been well studied. Therefore, we investigated TIL-expressing the B7-H1, PD-1, and FOXP3 molecules, in the microenvironment of human breast tumors and their possible association with the progression of the disease.

Methods: Using immunohistochemistry, tumor sections from 62 breast cancer patients were co-stained for B7-H1, PD-1 and FOXP3 molecules and their expression was statistically correlated with factors known to be involved in the progression of the disease.

Results: A co-existence of B7-H1+ T lymphocytes and FOXP3+ Tregs was evidenced by the highly significant correlation of these molecules (P < .0001) and their expression by different T lymphocyte subsets was clearly demonstrated. Interestingly, concomitant presence of FOXP3+ Tregs, B7-H1+ and PD-1+ TIL synergistically correlated with high histological grade (III) (P < .001), estrogen receptor negative status (P = .017), and the presence of severe lymphocytic infiltration (P = .022).

Conclusion: Accumulation of TIL-expressing such inhibitory molecules may deteriorate the immunity of high-risk breast cancer patients and this should encourage vigorous combinatorial immunotherapeutic approaches targeting Tregs and B7-H1/PD-1 molecules.

Show MeSH
Related in: MedlinePlus