Worse outcome in breast cancer with higher tumor-infiltrating FOXP3+ Tregs : a systematic review and meta-analysis

Abstract

BackgroundForkhead box P3(FOXP3) is known as the optimum maker for regulatory T cells(Tregs), which are conventionally thought to induce immune tolerance to disturb the antitumor immunity. However, the research on the prognostic significance of tumor-infiltrating FOXP3+ Tregs in breast cancer is still limited and the results are controversial.MethodsWe searched for studies in PubMed, EMBASE and Web of Science prior to January 2015. The correlation between FOXP3+ tumor-infiltrating lymphocytes(TILs) and breast cancer prognosis was analyzed. The meta-analysis was performed using STATA 11.0. Pooled hazard ratios (HRs) with 95 % confidence intervals (CIs) were used to estimate the degree of the association between FOXP3+ TILs and prognosis of breast cancers, while relative ratios (RRs) were used to evaluate the relationship between FOXP3+ TILs and clinicopathological features of breast cancers.ResultA total of 15 studies comprising 8666 breast cancer patients met the inclusion criteria. Our results showed that higher FOXP3+ TILs level was significantly associated with poor prognosis in terms of overall survival (OS) (pooled HR:1.60, 95 % CI:1.06–2.42; P < 0.05). We found that breast cancer with higher FOXP3+ TILs level was positively correlated with c-erbB-2 positive status (pooled RR:1.52, 95 % CI:1.32–1.75; P < 0.05), lymph node positive status(pooled RR:1.17, 95 % CI:1.04–1.32; P < 0.05) while there was a negative association with ER positive status(pooled RR:0.65, 95 % CI:0.56–0.76; P < 0.05) and PR positive status(pooled RR:0.66, 95 % CI:0.51–0.87; P < 0.05).ConclusionThe present results of meta-analysis showed that higher FOXP3+ TILs level in patients with breast cancer led to poor overall survival (OS) and was significantly associated with c-erbB-2 status, lymph node status, ER status and PR status. FOXP3+ TILs level is a promising prognostic factor in breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2732-0) contains supplementary material, which is available to authorized users.

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

“…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].…”

“…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].…”

Influence of opioids on immune function in patients with cancer pain: from bench to bedside

“…However, it should be noted that not all immune cells are beneficial to the anti‐tumour response. Immunosuppressive ‘regulatory’ T‐cell populations can suppress the immune response (Takeuchi and Nishikawa, ), and meta‐analyses have reported that increased regulatory T‐cell infiltration into breast cancers is associated with a poorer survival (Shou et al, ; Wang et al, ). Incubating blood from patients with gastric or breast cancer with morphine, sufentanil or fentanyl in vitro increases the number of regulatory T‐cells (Gong et al, ; Hou et al, ).…”

Evaluation of Inflammatory Cells (Tumor Infiltrating Lymphocytes) in Solid Tumors

“…Například přítom-nost FOXP3+ Treg je obecně asociována s horší prognózou a navíc je hladina Treg také spojena s dalšími nepřízni-vými prognostickými faktory, jako jsou grade, metastázy v lymfatických uzlinách, negativita estrogenních receptorů a pozitivita HER2 [57,58]. To ovšem platí jen pro estrogen pozitivní nádory, naopak u estrogen negativních nádorů má vyšší zastoupení FOXP3+ Treg lymfocytů prognosticky příznivý efekt jakožto marker aktivní imunitní odpovědi [59].…”