Prognostic impact of CD4-positive T cell subsets in early breast cancer: a study based on the FinHer trial patient population

Abstract

BackgroundThe clinical importance of tumor-infiltrating cluster of differentiation 4 (CD4) T cells is incompletely understood in early breast cancer. We investigated the clinical significance of CD4, forkhead box P3 (FOXP3), and B cell attracting chemokine leukocyte chemoattractant-ligand (C-X-C motif) 13 (CXCL13) in early breast cancer.MethodsThe study is based on the patient population of the randomized FinHer trial, where 1010 patients with early breast cancer were randomly allocated to adjuvant chemotherapy containing either docetaxel or vinorelbine, and human epidermal growth factor receptor 2 (HER2)-positive patients were also allocated to trastuzumab or no trastuzumab. Breast cancer CD4, FOXP3, and CXCL13 contents were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR), and their influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan-Meier estimates in the entire cohort and in selected molecular subgroups. Interactions between variables were analyzed using Cox regression. The triple-negative breast cancer (TNBC) subset of the HE10/97 randomized trial was used for confirmation.ResultsHigh CXCL13 was associated with favorable DDFS in univariable analysis, and independently in multivariable analysis (HR 0.44, 95% CI 0.29–0.67, P ≤ 0.001), most strongly in TNBC (HR 0.39, 95% CI 0.19–0.79, P = 0.009). No significant interaction with chemotherapy or trastuzumab administration was detected. Neither tumor CD4 content nor FOXP3 content was associated with DDFS. The favorable prognostic influence of CXCL13 was confirmed in the HE10/97 trial patient population with TNBC (HR 0.30, 95% CI 0.09–0.93; P = 0.038).ConclusionsThe results provide a high level of evidence that humoral immunity influences the survival outcomes of patients with early breast cancer, in particular of those with TNBC.Trial registrationThe study reports retrospective biomarker analyses in the prospective FinHer trial and the prospective HE10/97 trial.ISRCTN76560285. Registered on 18 March 2005.ACTRN12611000506998. Registered on 16 May 2011.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-0942-x) contains supplementary material, which is available to authorized users.

Prognostic Significance of Interferon-γ and Its Signaling Pathway in Early Breast Cancer Depends on the Molecular Subtypes

“…Furthermore, in a retrospective analysis of the FinHER trial, the B-cell attracting chemokine leukocyte chemoattractant–ligand (C–X–C motif) 13 (CXCL13) was independently associated with prognosis in triple-negative breast cancer. Other studies have also confirmed that B-cell signatures had a prognostic impact, particularly in basal-like and HER2-positive breast cancer subtypes [ 11 ]. In a further analysis, we examined the prognostic impact of different immune signatures in node-negative breast cancer patients and demonstrated a prognostic effect of a B-cell and T-cell signature, especially in HER2-positive breast cancer [ 12 ].…”

“…The B-cell metagene was correlated with improved outcomes in highly proliferating node-negative breast cancer patients regardless of ER or HER2 status [ 9 ]. In a further study evaluating CXCL13 mRNA expression in the FinHER trial, CXCL13 as a marker of the humoral immune system was associated with favorable prognosis, particularly in triple-negative breast cancer (TNBC) [ 11 ]. One possible explanation for the finding that immune-related gene signatures have prognostic and predictive effects, particularly in the case of strongly proliferating tumors, especially TNBC or basal-like breast cancer, is the occurrence of an increased mutation load and neoepitopes that can induce or enhance an antitumor immune response [ 18 , 19 ].…”

Immune microenvironment in ductal carcinoma in situ: a comparison with invasive carcinoma of the breast

“…It is well known that CD4+ TILs display a large degree of plasticity and the ability to differentiate into multiple sublineages in response to environmental cues [30]. CD4+ Th1 cells, CD4+ CTLs, and follicular helper T cells exert potent anti-tumor activity, whereas regulatory T cells or, under certain circumstances, CD4+ Th2 cells and CD4+ Th17 cells show tumor-promoting activity [30,31]. Thus, in further studies, analyses of CD4+ TIL subsets would be crucial to find the overall effect of heavy CD4+ TIL infiltration around HRnegative DCIS.…”

Prognostic impact of a tumor-infiltrating lymphocyte subtype in triple negative cancer of the breast

“…Since CD4 + TILs are expressed in many T cell subsets including T helper 1 (Th1) cells, T helper 2 (Th2) cells and Tregs, each of these may have a different impact on prognosis. Th1 cells secrete several cytokines such as interferon gamma (IFNg), transforming growth factor beta (TGFβ), tumor necrosis factor alpha (TNF), and interleukin 2 (IL-2) [31]. These cytokines are involved in the function of CD8 + TILs and protect against tumor development and progression.…”