Clinicopathological and prognostic significance of FOXP3+ tumor infiltrating lymphocytes in patients with breast cancer: a meta-analysis

Jiang, Daqing; Gao, Zhiqiang; Cai, Zhengang; Wang, Meixian; He, Jianjun

doi:10.1186/s12885-015-1742-7

Cited by 54 publications

(55 citation statements)

References 43 publications

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“…In agreement with previous findings, we demonstrated that both CD8+ and FOXP3+ cells were associated with good outcome in patients with TNBC, and that the clinical significance of FOXP3+ lymphocytes was highly dependent on the concurrent presence of cytotoxic T cells [23–27]. Interestingly, when stratified based on the presence of CD8+ lymphocytes, a high infiltration of FOXP3+ cells trended towards reduced survival in TNBC patients with low numbers of CD8+ cells.…”

Section: Discussionsupporting

confidence: 91%

An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers

et al. 2016

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BackgroundStromal tumor-infiltrating lymphocytes (TILs) are a robust prognostic factor in triple-negative breast cancer (TNBC). However, the clinical significance of TILs may be influenced by the complex landscape of the tumor immune microenvironment. In this study, we aimed to evaluate the composition and the functionality of lymphocytic infiltration and checkpoint receptors in TNBC.MethodsFormalin-fixed, paraffin-embedded tissues were retrospectively collected from a cohort of patients with early-stage TNBC treated with adjuvant anthracycline-based chemotherapy (n = 259). Results were validated in an independent cohort of patients with TNBC (n = 104). Stromal TILs were evaluated on hematoxylin-and-eosin-stained sections. The density of CD4+, CD8+, and FOXP3+ lymphocytes, and the expression of the immune checkpoints PD-1 and LAG-3, were assessed by immunohistochemical analysis.ResultsThe presence of elevated TILs positively correlated with the density of all T cell subtypes, especially cytotoxic CD8+ lymphocytes. We showed that increasing stromal TILs assessed as a continuous variable is an independent prognostic marker of prolonged relapse-free survival and overall survival in TNBC. Among immune subpopulations, CD8+ lymphocytes are the main effectors of anti-tumor immune responses. In two independent cohorts, we found that PD-1 and LAG-3 were concurrently expressed in approximately 15% of patients with TNBC. The expression of both checkpoint receptors positively correlated with the presence of TILs, but was not significantly associated with patient outcome.ConclusionsOverall, our data indicate that the evaluation of stromal TILs remains the most reliable immune prognostic marker in TNBC, and support the clinical evaluation of anti-PD-1/PD-L1 and anti-LAG-3 in a subset of patients with TNBC who have concurrent expression of both checkpoint receptors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0783-4) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers

et al. 2016

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“…A high Tregs level was associated with poor prognosis in breast cancer [43] but with improved prognosis in colorectal cancer [44]. This study addressed the prognostic value of Tregs in HCC.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic and prognostic significance of regulatory T cells in patients with hepatocellular carcinoma: a meta-analysis

Sun

Liao

et al. 2017

Oncotarget

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The clinicopathologic and prognostic significance of regulatory T cells (Tregs) in patients with hepatocellular carcinoma (HCC) remains controversial. We performed a meta-analysis to resolve this issue. PubMed, Embase, Cochrane library, and the Web of Science were searched to identify eligible studies performed up to November 2016. A total of 3,854 HCC patients from 27 cohort studies were included. The meta-analysis revealed that high levels of Tregs were associated with poor overall survival (OS; HR = 1.95, P < 0.00001) and disease-free survival (DFS; HR = 1.82, P < 0.00001). However, the prognostic effect varied greatly according to the site of the Tregs. Higher intratumoral and peripheral blood levels of Tregs were associated with shorter OS and DFS, whereas a high peritumoral Tregs level was not associated with decreased OS and DFS. Trial design, therapy and method of detection had no effect on prognosis of Tregs. Moreover, the patients with high Tregs infiltration had multiple tumors, high AFP level, poor differentiation, later TNM stage, and vascular invasion. The present study demonstrates that high levels of intratumoral and peripheral blood Tregs predict multiple tumors, high AFP level, poor differentiation, later TNM stage, and vascular invasion and might be a promising prognostic factor in patients with HCC.

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“…Whilst many of the included studies follow the TIL scoring method used by Denkert in 2010 [60], there is variation with some studies using H&E assessment [14,58,59,61,62,65], some using immunohistochemistry [63,64], and others using mRNA expression profiling [63]. Conclusions from some recent meta-analyses in this field [66,67] indicate that care must be taken when interpreting the results of studies of prognostic biomarkers. For example, it is suggested that FOXP3 + T regs correlate with poor prognosis in breast cancer [66,67], however T reg levels also correlate with other poor prognostic factors such as estrogen receptor-negativity, HER2-positivity, lymph node metastasis and high histological grade [68–71].…”

Section: Tils In Invasive Breast Carcinomamentioning

confidence: 99%

“…Conclusions from some recent meta-analyses in this field [66,67] indicate that care must be taken when interpreting the results of studies of prognostic biomarkers. For example, it is suggested that FOXP3 + T regs correlate with poor prognosis in breast cancer [66,67], however T reg levels also correlate with other poor prognostic factors such as estrogen receptor-negativity, HER2-positivity, lymph node metastasis and high histological grade [68–71]. Within the estrogen receptor-negative subgroup, high levels of FOXP3 + T regs may actually correlate with improved prognosis as markers of an active immune response [68,70].…”

Section: Tils In Invasive Breast Carcinomamentioning

confidence: 99%

Assessing Tumor-infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method From the International Immunooncology Biomarkers Working Group: Part 1: Assessing the Host Immune Response, TILs in Invasive Breast Carcinoma and Ductal Carcinoma In Situ, Metastatic Tumor Deposits and Areas for Further Research

Hendry

Salgado

Gevaert

et al. 2017

Advances in Anatomic Pathology

524

374

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Assessment of tumor infiltrating lymphocytes (TILs) in histopathological specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible and reliable immuno-oncology biomarkers is clear. In Part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on H&E sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in Part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.

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Clinicopathological and prognostic significance of FOXP3+ tumor infiltrating lymphocytes in patients with breast cancer: a meta-analysis

Cited by 54 publications

References 43 publications

An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers

An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers

Clinicopathologic and prognostic significance of regulatory T cells in patients with hepatocellular carcinoma: a meta-analysis

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