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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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Correlations between FOXP3+ Tregs, B7-H1+ TIL and PD-1+ TIL. (A) statistical analysis of FOXP3+ Tregs infiltration in tumor tissues with B7-H1+ TIL, as analyzed with ANOVA of three groups of breast cancer patients with different FOXP3+ Tregs infiltration (Low = 0 to 4%, Medium = 5 to 14% and High 15% and above of total CD3+ TIL), (B) their linear correlation analysis and (C) statistical analysis of FOXP3+ Tregs infiltration with PD-1+ TIL in breast cancer as analyzed with ANOVA of three groups of breast cancer patients with different FOXP3+ Tregs infiltration (Low = 0 to 4%, Medium = 5 to 14% and High 15% and above of total CD3+ TIL).
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Figure 3: Correlations between FOXP3+ Tregs, B7-H1+ TIL and PD-1+ TIL. (A) statistical analysis of FOXP3+ Tregs infiltration in tumor tissues with B7-H1+ TIL, as analyzed with ANOVA of three groups of breast cancer patients with different FOXP3+ Tregs infiltration (Low = 0 to 4%, Medium = 5 to 14% and High 15% and above of total CD3+ TIL), (B) their linear correlation analysis and (C) statistical analysis of FOXP3+ Tregs infiltration with PD-1+ TIL in breast cancer as analyzed with ANOVA of three groups of breast cancer patients with different FOXP3+ Tregs infiltration (Low = 0 to 4%, Medium = 5 to 14% and High 15% and above of total CD3+ TIL).

Mentions: We have found that B7-H1+, PD-1+ TIL and FOXP3+ Tregs were significantly associated with similar bad prognostic factors. Therefore, we further investigated the correlation between B7-H1+ TIL or PD-1+ TIL and FOXP3+ Tregs infiltration in breast tumors. There was a highly significant correlation between the expression of B7-H1 in TIL and intratumoral FOXP3+ Tregs (P < .0001) as shown by ANOVA test (Figure 3A) and by linear regression analysis (P < .004 and R2 = 0.3) (Figure 3B). There was also a significant correlation between FOXP3+ Tregs infiltration and PD-1 expression in TIL (P = .007) as shown by ANOVA (Figure 3C).


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)

Correlations between FOXP3+ Tregs, B7-H1+ TIL and PD-1+ TIL. (A) statistical analysis of FOXP3+ Tregs infiltration in tumor tissues with B7-H1+ TIL, as analyzed with ANOVA of three groups of breast cancer patients with different FOXP3+ Tregs infiltration (Low = 0 to 4%, Medium = 5 to 14% and High 15% and above of total CD3+ TIL), (B) their linear correlation analysis and (C) statistical analysis of FOXP3+ Tregs infiltration with PD-1+ TIL in breast cancer as analyzed with ANOVA of three groups of breast cancer patients with different FOXP3+ Tregs infiltration (Low = 0 to 4%, Medium = 5 to 14% and High 15% and above of total CD3+ TIL).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Correlations between FOXP3+ Tregs, B7-H1+ TIL and PD-1+ TIL. (A) statistical analysis of FOXP3+ Tregs infiltration in tumor tissues with B7-H1+ TIL, as analyzed with ANOVA of three groups of breast cancer patients with different FOXP3+ Tregs infiltration (Low = 0 to 4%, Medium = 5 to 14% and High 15% and above of total CD3+ TIL), (B) their linear correlation analysis and (C) statistical analysis of FOXP3+ Tregs infiltration with PD-1+ TIL in breast cancer as analyzed with ANOVA of three groups of breast cancer patients with different FOXP3+ Tregs infiltration (Low = 0 to 4%, Medium = 5 to 14% and High 15% and above of total CD3+ TIL).
Mentions: We have found that B7-H1+, PD-1+ TIL and FOXP3+ Tregs were significantly associated with similar bad prognostic factors. Therefore, we further investigated the correlation between B7-H1+ TIL or PD-1+ TIL and FOXP3+ Tregs infiltration in breast tumors. There was a highly significant correlation between the expression of B7-H1 in TIL and intratumoral FOXP3+ Tregs (P < .0001) as shown by ANOVA test (Figure 3A) and by linear regression analysis (P < .004 and R2 = 0.3) (Figure 3B). There was also a significant correlation between FOXP3+ Tregs infiltration and PD-1 expression in TIL (P = .007) as shown by ANOVA (Figure 3C).

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