A low number of tumor-infiltrating FOXP3-positive cells during primary systemic chemotherapy correlates with favorable anti-tumor response in patients with breast cancer

Current understanding of the role of several cancer risk factors is more comprehensive, as reported for a number of sites, including the brain, colon, breasts, and ovaries. Despite such advances, the incidence of breast cancer continues to increase worldwide. Signals from the microenviroment have a profound influence on the maintenance or progression cancers. Although T cells present the most important immunological response in tumor growth in the early stages of cancer, they become suppressive CD4(+) and CD8(+) regulatory T cells (Tregs) after chronic stimulation and interactions with tumor cells, thus promoting rather than inhibiting cancer development and progression. Tregs have an important marker protein which is FoxP3, though it does not necessarily confer a Treg phenotype when expressed in CD4(+) T lymphocytes. High Treg levels have been reported in peripheral blood, lymph nodes, and tumor specimens from patients with different types of cancer. The precise mechanisms by which Tregs suppress immune cell functions remain unclear, and there are reports of both direct inhibition through cell-cell contact and indirect inhibition through the secretion of anti-inflammatory mediators such as interleukin. In this review, we present the molecular and immunological aspects of Treg cells in the metastasis of breast cancer.

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“…They demonstrated that lymph vessel invasion was prominent in the group with a high number of FoxP3 infiltrates [79].…”

Section: Possible Functions Of the T Cells In Disseminated Breast Cancermentioning

confidence: 99%

Regulatory T cells and breast cancer: implications for immunopathogenesis

Watanabe

Oda

Amarante

et al. 2010

Cancer Metastasis Rev

110

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“…To date, several studies of breast cancer have shown a consistent association between FOXP3 + TIL and poor clinical outcome (Bates et al , 2006; Aruga et al , 2009; Gobert et al , 2009; Liu et al , 2011; Yan et al , 2011; Mahmoud et al , 2011b). Although none of these studies focused on specific histological or molecular subtypes of breast cancer, FOXP3 + TIL showed a consistent association with ER-negative (ER–) tumours, which are biologically and clinically distinct from ER+ lesions (Foulkes et al , 2010).…”

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confidence: 99%

Tumour-infiltrating FOXP3+ lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer

et al. 2012

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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.

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“…In the end, we reviewed 58 studies encompassing 16 different cancer types (Table 1), including bladder (19), breast (21)(22)(23)(24)(25)(26)(27)(28), cervical (29,30), colorectal (12,(31)(32)(33)(34)(35)(36)(37)(38)(39), endometrial (40)(41)(42), gastric (14,(43)(44)(45)(46), head and neck (47), hepatocellular (48)(49)(50)(51)(52), lung (53,54), melanoma (55)(56)(57)(58), mesothelial (59), oral (4,(60)(61)(62)(63), ovarian (2,3,…”

Section: Introductionmentioning

confidence: 99%

The Prognostic Value of FoxP3+ Tumor-Infiltrating Lymphocytes in Cancer: A Critical Review of the Literature

deLeeuw

Kost

Kakal

et al. 2012

Clinical Cancer Research

394

307

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CD8þ tumor-infiltrating lymphocytes (TIL) are associated with survival in a variety of cancers. A second subpopulation of TIL, defined by forkhead box protein P3 (FoxP3) expression, has been reported to inhibit tumor immunity, resulting in decreased patient survival. On the basis of this premise, several groups are attempting to deplete FoxP3þ T cells to enhance tumor immunity. However, recent studies have challenged this paradigm by showing that FoxP3þ T cells exhibit heterogeneous phenotypes and, in some cohorts, are associated with favorable prognosis. These discrepant results could arise from differences in study methodologies or the biologic properties of specific cancer types. Here, we conduct the first systematic review of the prognostic significance of FoxP3þ T cells across nonlymphoid cancers (58 studies from 16 cancers). We assessed antibody specificity, cell-scoring strategy, multivariate modeling, use of single compared with multiple markers, and tumor site. Two factors proved important. First, when FoxP3 was combined with one additional marker, double-positive T cells were generally associated with poor prognosis. Second, tumor site had a major influence. FoxP3þ T cells were associated with poor prognosis in hepatocellular cancer and generally good prognosis in colorectal cancer, whereas other cancer types were inconsistent or understudied. We conclude that FoxP3þ T cells have heterogeneous properties that can be discerned by the use of additional markers. Furthermore, the net biologic effects of FoxP3þ T cells seem to depend on the tumor site, perhaps reflecting microenvironmental differences. Thus, depletion of FoxP3þ T cells might enhance tumor immunity in some patient groups but be detrimental in others.

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A low number of tumor-infiltrating FOXP3-positive cells during primary systemic chemotherapy correlates with favorable anti-tumor response in patients with breast cancer

Cited by 30 publications

References 11 publications

Regulatory T cells and breast cancer: implications for immunopathogenesis

Regulatory T cells and breast cancer: implications for immunopathogenesis

Tumour-infiltrating FOXP3+ lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer

The Prognostic Value of FoxP3+ Tumor-Infiltrating Lymphocytes in Cancer: A Critical Review of the Literature

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