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PD-L1 mediated the differentiation of tumor-infiltrating CD19(+) B lymphocytes and T cells in Invasive breast cancer.

ABSTRACT: Accumulating evidence suggests that B cells play important roles in inhibiting the immune response in autoimmune disorders and human tumors as well as murine tumor models. In an effort to explore the role of B cells in human breast cancer etiology, we examined the presence of CD19(+) B lymphocytes in 134 cases of invasive breast carcinoma (IBCa) and 31 breast fibroadenoma, and assessed its relationship with PD-L1 (programmed death-ligand 1) expression in breast cancer. We found that the density of CD19(+) B lymphocytes was higher in IBCa compared with fibroadenoma, and significantly associated with increasing tumor grade, negative estrogen status. Similar findings were observed for the expression of IL-10 in IBCa. Meanwhile, CD19(+) B lymphocytes were shown to be highly coincident with PD-L1 and IL-10 in IBCa. We further demonstrated that CD19(+) B cells can differentiate into CD19(+)CD24(+)CD38(+) B cells when co-cultured with PD-L1(hi) MDA-MB231 cells. In addition, the percentage of CD19(+)CD24(+)CD38(+) B cells was higher in breast tissue and peripheral blood cells of IBCa patients than that of benign tumor and health individuals. And CD19(+)CD24(+)CD38(+) B cells were found to be IL-10 secreting B cells. Finally, we showed that CD19(+) B cells from IBCa patients but not healthy individuals induced formation of CD4(+)CD25(+)Foxp3(+) T cells when co-cultured with T cells from IBCa patients and healthy subjects (80.4% and 30.8% respectively). The induction of CD4(+)CD25(+)Foxp3(+) T cells by CD19(+) B cells was further shown to be mediated by PD-L1. Together, these results are suggestive of a role for CD19(+) B lymphocytes in immune suppression and tumor evasion via PD-L1 in breast cancer.

SUBMITTER: Guan H

PROVIDER: S-EPMC4801469 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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PD-L1 mediated the differentiation of tumor-infiltrating CD19<sup>+</sup> B lymphocytes and T cells in Invasive breast cancer.

Guan Honggeng H Lan Yang Y Wan Yuqiu Y Wang Qin Q Wang Cheng C Xu Longjiang L Chen Yongjing Y Liu Wenting W Zhang Xueguang X Li Yecheng Y Gu Yongping Y Wang Zemin Z Xie Fang F

Oncoimmunology 20150812 2

Accumulating evidence suggests that B cells play important roles in inhibiting the immune response in autoimmune disorders and human tumors as well as murine tumor models. In an effort to explore the role of B cells in human breast cancer etiology, we examined the presence of CD19<sup>+</sup> B lymphocytes in 134 cases of invasive breast carcinoma (IBCa) and 31 breast fibroadenoma, and assessed its relationship with PD-L1 (programmed death-ligand 1) expression in breast cancer. We found that the ...[more]

PMID: 27057444

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Project description:BackgroundThe H&E stromal tumor-infiltrating lymphocyte (sTIL) score and programmed death ligand 1 (PD-L1) SP142 immunohistochemistry assay are prognostic and predictive in early-stage breast cancer, but are operator-dependent and may have insufficient precision to characterize dynamic changes in sTILs/PD-L1 in the context of clinical research. We illustrate how multiplex immunofluorescence (mIF) combined with statistical modeling can be used to precisely estimate dynamic changes in sTIL score, PD-L1 expression, and other immune variables from a single paraffin-embedded slide, thus enabling comprehensive characterization of activity of novel immunotherapy agents.MethodsSerial tissue was obtained from a recent clinical trial evaluating loco-regional cytokine delivery as a strategy to promote immune cell infiltration and activation in breast tumors. Pre-treatment biopsies and post-treatment tumor resections were analyzed by mIF (PerkinElmer Vectra) using an antibody panel that characterized tumor cells (cytokeratin-positive), immune cells (CD3, CD8, CD163, FoxP3), and PD-L1 expression. mIF estimates of sTIL score and PD-L1 expression were compared to the H&E/SP142 clinical assays. Hierarchical linear modeling was utilized to compare pre- and post-treatment immune cell expression, account for correlation of time-dependent measurement, variation across high-powered magnification views within each subject, and variation between subjects. Simulation methods (Monte Carlo, bootstrapping) were used to evaluate the impact of model and tissue sample size on statistical power.ResultsmIF estimates of sTIL and PD-L1 expression were strongly correlated with their respective clinical assays (p < .001). Hierarchical linear modeling resulted in more precise estimates of treatment-related increases in sTIL, PD-L1, and other metrics such as CD8+ tumor nest infiltration. Statistical precision was dependent on adequate tissue sampling, with at least 15 high-powered fields recommended per specimen. Compared to conventional t-testing of means, hierarchical linear modeling was associated with substantial reductions in enrollment size required (n = 25➔n = 13) to detect the observed increases in sTIL/PD-L1.ConclusionmIF is useful for quantifying treatment-related dynamic changes in sTILs/PD-L1 and is concordant with clinical assays, but with greater precision. Hierarchical linear modeling can mitigate the effects of intratumoral heterogeneity on immune cell count estimations, allowing for more efficient detection of treatment-related pharmocodynamic effects in the context of clinical trials.Trial registrationNCT02950259 .

Dataset Information

PD-L1 mediated the differentiation of tumor-infiltrating CD19(+) B lymphocytes and T cells in Invasive breast cancer.

Publications

PD-L1 mediated the differentiation of tumor-infiltrating CD19<sup>+</sup> B lymphocytes and T cells in Invasive breast cancer.

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