Bohling SD, Allison KHImmunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target. Mod Pathol 21(12): 1527-1532

Department of Anatomic Pathology, University of Washington Medical Center, Seattle, WA 98195-6100, USA.
Modern Pathology (Impact Factor: 6.19). 10/2008; 21(12):1527-32. DOI: 10.1038/modpathol.2008.160
Source: PubMed


FoxP3 is a marker for immunosuppressive CD25+CD4+ regulatory T cells. These regulatory T cells are thought to play a role in inducing immune tolerance to antigens and may be selectively recruited by carcinomas. We investigated whether breast carcinomas had significant numbers of FoxP3-positive regulatory T cells by immunohistochemistry, and if their presence was associated with other prognostic factors, such as Nottingham grade, hormone receptor immunohistochemical profile, tumor size, or lymph node metastases. Ninety-seven needle core or excisional breast biopsies with invasive breast carcinoma diagnosed at the University of Washington were stained with antibodies to FoxP3, estrogen receptor, and Her2/neu. The numbers of FoxP3-positive cells present within the neoplastic epithelium, and immediately adjacent stroma were counted manually in three high-powered fields (HPFs; × 400) by two independent pathologists. The average scores were then correlated with the parameters of interest. A threshold of ≥15 FoxP3-positive cells/HPF was used to define a FoxP3-positive case in some analyses. Higher average numbers of FoxP3-positive cells present significantly correlated with higher Nottingham grade status (P=0.000229). In addition, the presence of significant numbers (≥15/HPF) of FoxP3-positive cells in breast carcinoma was positively associated with higher Nottingham grade (P=0.00002585). Higher average numbers of FoxP3-positive cells were also significantly associated with larger tumor size (>2.0 cm; P=0.012824) and trended toward an association with estrogen receptor negativity. Interestingly, 'triple-negative' (estrogen and progesterone receptor negative and Her2/neu negative) Nottingham grade III cases were also significantly associated with high numbers of FoxP3 cells. These results argue that regulatory T cells may play a role in inducing immune tolerance to higher grade, more aggressive breast carcinomas, and are a potential therapeutic target for these cancers.

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    • "In both the tumor periphery and tumor bed, unfavorable pathological parameters (a Ki-67 LI of ≥14%, a worse histologic grade and nuclear grade, tumor recurrence, and aggressive biologic subtype [TNBC]) were associated with more Foxp3 Treg infiltration. These results are in agreement with those of previous studies reporting the correlation between increased Foxp3 Treg infiltration and unfavorable pathologic phenotypes in breast cancer [12,13,14]. "
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    ABSTRACT: Forkhead box P3 (Foxp3) is known as the most specific marker for regulatory T lymphocytes, which play an important role in immune tolerance to disturb antitumor immunity. The present study aimed to investigate the prognostic significance of Foxp3 regulatory T lymphocyte (Foxp3 Treg) infiltration in breast cancer. Immunohistochemical studies with Foxp3, CD4, and CD8 were performed on representative full tissue sections from 143 patients with invasive ductal carcinoma, not otherwise specified. Foxp3 Treg infiltration and the ratios between Foxp3 Treg and CD4 or CD8 T cells were separately analyzed for the tumor bed and tumor periphery to evaluate their association with different clinicopathological parameters and patients' outcome. The tumor periphery was considerably more densely infiltrated by Foxp3 Treg, CD4, and CD8 T cells than the tumor bed. Unfavorable clinicopathological parameters (a Ki-67 labeling index of ≥14%, a worse histologic grade, a worse nuclear grade, hormone receptor negativity, human epidermal growth factor receptor 2 positivity, and tumor recurrence) were associated with increased Foxp3 Treg infiltration and a high ratio between Foxp3 Treg and CD4/CD8 T cells. In the tumor periphery, as Foxp3 Treg infiltration and the Foxp3 Treg/CD8 ratio increased, patients' 5-year disease-free survival rate decreased. The infiltration densities of Foxp3 Treg, CD4, and CD8 T cells were markedly different between the tumor bed and periphery. Besides the absolute count of Foxp3 Treg, the ratio between Foxp3 Treg and effector T cells was a significant prognostic factor in breast cancer.
    Journal of Breast Cancer 03/2014; 17(1):8-17. DOI:10.4048/jbc.2014.17.1.8 · 1.58 Impact Factor
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    • "Forkhead box P3 (FOXP3)-expressing Treg cells are a potent mediator of peripheral immune tolerance and suppress a wide range of immune cells, including CD4 + and CD8 + T cells, NK cells, NKT cells, B cells, and antigen presenting cells, through suppression of target cell activation, proliferation, and effector functions (Shevach, 2009; Sakaguchi et al., 2010; Jiang and Shapiro, 2014). Infiltration of Treg cells into breast cancers has been observed in numerous studies, and the number of Treg cells in the tumor site has been shown to be associated with a worse prognosis (Bates et al., 2006; Bohling and Allison, 2008; Ohara et al., 2009). Circulating Treg cells can be recruited to a breast cancer site through multiple signaling axes, including PGE2/EP2 (EP4), CCL22/CCR4, SDF1/ CXCR4, and CCL5/CCR1 (Gobert et al., 2009; Tan et al., 2011; Yan et al., 2011; Karavitis et al., 2012). "
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    • "Although none of these studies focused on specific histological or molecular subtypes of breast cancer, FOXP3 þ TIL showed a consistent association with ER-negative (ER–) tumours, which are biologically and clinically distinct from ER þ lesions (Foulkes et al, 2010). Because TIL have been shown to associate with good outcome primarily in ER– tumours (Teschendorff et al, 2007; Desmedt et al, 2008; Calabro et al, 2009; Rody et al, 2009), and because FOXP3 þ TIL are inherently associated with ER negativity (Bates et al, 2006; Bohling and Allison, 2008; Ghebeh et al, 2008; Aruga et al, 2009; Liu et al, 2011; Mahmoud et al, 2011b; Yan et al, 2011), we chose to investigate the clinical impact of FOXP3 þ TIL in ER– breast cancer. Importantly, we found that high numbers of FOXP3 þ TIL are associated with dense infiltrates of CD8 þ TIL and favourable prognosis. "
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    ABSTRACT: Background: Regulatory T cells (Tregs) are commonly identified by expression of the transcription factor FOXP3 and are conventionally thought to promote cancer progression by suppressing anti-tumour immune responses. We examined the relationship between FOXP3+ tumour-infiltrating lymphocytes (TIL) and prognosis in oestrogen receptor (ER)-negative breast cancer, a tumour subtype with poor clinical outcome in which TIL are abundant. Methods: FOXP3+ and CD8+ TIL were assessed by immunohistochemistry in a cohort of 175 ER– breast tumours. Results were confirmed in an independent data set of 78 ER– breast tumours with publically available gene expression data. Results: High FOXP3+ TIL levels were strongly associated with prolonged recurrence-free survival (HR=0.461, P=0.0002), particularly among basal-like tumours (HR=0.280, P=0.0001), for which FOXP3 status was independent of standard prognostic factors. Over 75% of FOXP3+ TIL in triple negative breast tumours displayed a conventional CD4+CD25+ Treg phenotype. Importantly, FOXP3+ TIL were positively correlated with CD8+ (cytotoxic) T cells (rs=0.76, P<0.0001), and were prognostically insignificant in tumours with low levels of CD8+ TIL. These observations were confirmed in an independent cohort. Conclusion: In contrast with current dogma, we show for the first time that FOXP3+ TIL are associated with robust anti-tumour immunity and favourable prognosis in ER– breast cancer.
    British Journal of Cancer 11/2012; 108(1). DOI:10.1038/bjc.2012.524 · 4.84 Impact Factor
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