Research Papers:

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

In Hae Park, Han Na Yang, Kyoung Joo Lee, Tae-Sik Kim, Eun Sook Lee, So-Youn Jung, Youngmee Kwon and Sun-Young Kong _

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Oncotarget. 2017; 8:32722-32730. https://doi.org/10.18632/oncotarget.16281

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In Hae Park1,2, Han Na Yang2, Kyoung Joo Lee3, Tae-Sik Kim4, Eun Sook Lee1, So-Youn Jung1,2, Youngmee Kwon1,2, Sun-Young Kong3,4,5

1Center for Breast Cancer, National Cancer Center, Korea

2Breast and Endocrine Cancer Branch of Research Institute, National Cancer Center, Korea

3Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Korea

4Translational Epidemiology Research Branch, Research Institute, National Cancer Center, Korea

5Department of Laboratory Medicine, Hospital, National Cancer Center, Korea

Correspondence to:

Sun-Young Kong, email: [email protected]

Keywords: IL-18, NK cells, breast cancer, hormone receptor, PD-1

Received: September 30, 2016     Accepted: March 09, 2017     Published: March 16, 2017


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.

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