Dataset Information

Tumor-derived IL-18 induces PD-1 expression on immunosuppressive NK cells in triple-negative breast cancer.

ABSTRACT:

Purpose

While the inflammatory cytokine interleukin-18 (IL-18) is known to activate natural killer (NK) cells, its precise role in cancer is controversial. In this study, we investigated the role of tumor-derived IL-18 on peripheral blood NK cells in breast cancer patients.

Results

In breast cancer cell lines, IL-18 was expressed and secreted in the triple-negative breast cancer (TNBC) cell lines MDA-MB-231 and HCC-70 but not in MCF-7 cells. The immature and non-cytotoxic CD56dimCD16dim/- NK cell fraction was increased following co-culture with MDA-MB-231 cells, and this increase was not observed with tumor cells transfected with siRNA for IL-18 or in MCF-7 cells. In addition, tumor-derived IL-18 increased PD-1 expression on CD56dimCD16dim/- NK cells, although no effect on PD-L1 expression in tumor cells was observed. Among EBC patients, serum IL-18 levels were significantly increased in those with a TNBC subtype compared to levels from patients with other subtypes, and the IL-18 levels were strongly associated with poor survival. Similarly, serum IL-18 and CD56dimCD16dim/- NK cells were also increased in patients with metastatic TNBC who had progressive disease following cytotoxic chemotherapy.

Experimental design

We performed in vitro experiments in breast cancer cell lines, measured cytokine levels by RT-qPCR, western blot, and ELISA, and analyzed NK cell subsets by flow cytometry. For clinical validation, we collected and analyzed blood sample from patients with early breast cancer (EBC, N = 545) and metastatic breast cancer (MBC, N = 42).

Conclusions

Our data revealed that tumor-derived IL-18 is associated with bad prognosis in patients with TNBC. Tumor-derived IL-18 increased the immunosuppressive CD56dimCD16dim/- NK cell fraction and induced PD-1 expression on these NK cells.

SUBMITTER: Park IH

PROVIDER: S-EPMC5464822 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Publications

Tumor-derived IL-18 induces PD-1 expression on immunosuppressive NK cells in triple-negative breast cancer.

Park In Hae IH Yang Han Na HN Lee Kyoung Joo KJ Kim Tae-Sik TS Lee Eun Sook ES Jung So-Youn SY Kwon Youngmee Y Kong Sun-Young SY

Oncotarget 20170501 20

<h4>Purpose</h4>While the inflammatory cytokine interleukin-18 (IL-18) is known to activate natural killer (NK) cells, its precise role in cancer is controversial. In this study, we investigated the role of tumor-derived IL-18 on peripheral blood NK cells in breast cancer patients.<h4>Results</h4>In breast cancer cell lines, IL-18 was expressed and secreted in the triple-negative breast cancer (TNBC) cell lines MDA-MB-231 and HCC-70 but not in MCF-7 cells. The immature and non-cytotoxic CD56dimC ...[more]

PMID: 28415798

Similar Datasets

Project description:BackgroundTriple negative breast cancer (TNBC) is an aggressive breast cancer for which there is currently no targeted therapy. Tumor-infiltrating B-cells (TIB) have been observed in tumor tissues of TNBC patients, but their functional role is unclear. IgG4 is one of four antibody subclasses of IgG expressed and secreted by B cells. Unlike other IgG isotypes, IgG4 has an immunosuppressive function and is induced by Th2-type cytokines. In cancers such as melanoma, IgG4 has been linked with advanced disease and poor patient survival. Therefore, we sought to determine if IgG4 + B cells are present and determine the mechanisms driving isotype switching in TNBC.MethodsWe performed co-culture assays to examine expression of Th2 cytokines by TNBC cells with and without the presence of B cells. We also performed in vitro class switching experiments with peripheral B cells with and without co-culture with TNBC cells in the presence or absence of an IL-10 blocking antibody. We examined expression of CD20+ TIB, IgG4 and Th2 cytokines by immunohistochemistry in 152 TNBC samples. Statistical analysis was done using Log-Rank and Cox-proportional hazards tests.ResultsOur findings indicate that B cells interact with TNBC to drive chronic inflammatory responses through increased expression of inflammatory cytokines including the TH2 cytokines IL-4 and IL-10. In vitro class switching studies show that interactions between TNBC cell lines and B cells drive isotype switching to the IgG4 isotype in an IL-10 dependent manner. In patient tissues, expression of IgG4 correlates with CD20 and tumor expression of IL-10. Both IgG4 and tumor IL-10 are associated to shorter recurrence free survival (RFS) and overall survival (OS) in TNBC. In a multi-variant analysis, IL-10 was associated with poor outcomes indicating that tumor IL-10 may drive immune escape.ConclusionsThese findings indicate that interactions between TIB and TNBC results in activation of chronic inflammatory signals such as IL-10 and IL-4 that drive class switching to an IgG4 + subtype which may suppress antibody driven immune responses. The presence of IgG4 + B cells may serve as a biomarker for poor prognosis.

Dataset Information

Tumor-derived IL-18 induces PD-1 expression on immunosuppressive NK cells in triple-negative breast cancer.

Purpose

Results

Experimental design

Conclusions

Publications

Tumor-derived IL-18 induces PD-1 expression on immunosuppressive NK cells in triple-negative breast cancer.

Similar Datasets

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