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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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Immunohistochemical staining of FOXP3+ Tregs B7-H1 +and PD-1+ in T lymphocytes of breast tissues. Representative micrographs at × 530 magnification of (A&D) CD3/FOXP3 double staining (red color, membranous for CD3 and brown nuclear color for FOXP3 expression). (B&E) B7-H1 single staining (brown color, membranous/cytoplasmic expression). (C&F) PD-1 single staining (brown color, membranous expression). Upper panel (A-C) is sections for normal breast duct and lower panel (D-F) is sections for infiltrating ductal carcinoma of the breast.
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Figure 1: Immunohistochemical staining of FOXP3+ Tregs B7-H1 +and PD-1+ in T lymphocytes of breast tissues. Representative micrographs at × 530 magnification of (A&D) CD3/FOXP3 double staining (red color, membranous for CD3 and brown nuclear color for FOXP3 expression). (B&E) B7-H1 single staining (brown color, membranous/cytoplasmic expression). (C&F) PD-1 single staining (brown color, membranous expression). Upper panel (A-C) is sections for normal breast duct and lower panel (D-F) is sections for infiltrating ductal carcinoma of the breast.

Mentions: In order to determine the frequencies of Tregs, B7-H1 and PD-1 expressing-T lymphocytes in normal breast tissues we stained sections obtained from breast patients undergoing plastic surgery (BP) as well as normal breast tissues adjacent to breast cancer tumors (N) for the expression of FOXP3, B7-H1 and PD-1 molecules. There were a few T lymphocytes in both N and BP in which FOXP3+ Tregs represented <5% of the total CD3+ TIL (Figure 1A). Similarly, T lymphocytes in normal tissues were negative for B7-H1 (Figure 1B). However, PD-1+ T lymphocytes were abundant in normal tissues with up to 30% of CD3+ cells co-expressing the PD-1 molecule (Figure 1C). In contrast to normal breast tissues, 56% of breast cancer patients had a higher Tregs frequency in their tumor tissues in which 5–50% of CD3+ TILs were Tregs (Figure 1D). Similarly, B7-H1 was expressed in TILs of 54% of breast cancer patients' tumor tissues in which 5–80% of TILs express this molecule. B7-H1 expression was not restricted to T lymphocytes as 30% of breast cancer patients showed also B7-H1 expression in their tumor cells (Figure 1E). This result was also described in our previous study [18]. The PD-1 molecule was expressed in TILs in 60% of the patients in which 5–70% of TIL express this molecule (Figure 1F). The expression pattern of the PD-1 molecule was membranous and restricted to T lymphocytes only.


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 of FOXP3+ Tregs B7-H1 +and PD-1+ in T lymphocytes of breast tissues. Representative micrographs at × 530 magnification of (A&D) CD3/FOXP3 double staining (red color, membranous for CD3 and brown nuclear color for FOXP3 expression). (B&E) B7-H1 single staining (brown color, membranous/cytoplasmic expression). (C&F) PD-1 single staining (brown color, membranous expression). Upper panel (A-C) is sections for normal breast duct and lower panel (D-F) is sections for infiltrating ductal carcinoma of the breast.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Immunohistochemical staining of FOXP3+ Tregs B7-H1 +and PD-1+ in T lymphocytes of breast tissues. Representative micrographs at × 530 magnification of (A&D) CD3/FOXP3 double staining (red color, membranous for CD3 and brown nuclear color for FOXP3 expression). (B&E) B7-H1 single staining (brown color, membranous/cytoplasmic expression). (C&F) PD-1 single staining (brown color, membranous expression). Upper panel (A-C) is sections for normal breast duct and lower panel (D-F) is sections for infiltrating ductal carcinoma of the breast.
Mentions: In order to determine the frequencies of Tregs, B7-H1 and PD-1 expressing-T lymphocytes in normal breast tissues we stained sections obtained from breast patients undergoing plastic surgery (BP) as well as normal breast tissues adjacent to breast cancer tumors (N) for the expression of FOXP3, B7-H1 and PD-1 molecules. There were a few T lymphocytes in both N and BP in which FOXP3+ Tregs represented <5% of the total CD3+ TIL (Figure 1A). Similarly, T lymphocytes in normal tissues were negative for B7-H1 (Figure 1B). However, PD-1+ T lymphocytes were abundant in normal tissues with up to 30% of CD3+ cells co-expressing the PD-1 molecule (Figure 1C). In contrast to normal breast tissues, 56% of breast cancer patients had a higher Tregs frequency in their tumor tissues in which 5–50% of CD3+ TILs were Tregs (Figure 1D). Similarly, B7-H1 was expressed in TILs of 54% of breast cancer patients' tumor tissues in which 5–80% of TILs express this molecule. B7-H1 expression was not restricted to T lymphocytes as 30% of breast cancer patients showed also B7-H1 expression in their tumor cells (Figure 1E). This result was also described in our previous study [18]. The PD-1 molecule was expressed in TILs in 60% of the patients in which 5–70% of TIL express this molecule (Figure 1F). The expression pattern of the PD-1 molecule was membranous and restricted to T lymphocytes only.

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