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22.08.2018 | Original Article | Ausgabe 12/2018

Cancer Immunology, Immunotherapy 12/2018

Anergic natural killer cells educated by tumor cells are associated with a poor prognosis in patients with advanced pancreatic ductal adenocarcinoma

Cancer Immunology, Immunotherapy > Ausgabe 12/2018
Chao Yang, He Cheng, Yiyin Zhang, Kun Fan, Guopei Luo, Zhiyao Fan, Qiuyi Huang, Yu Lu, Kaizhou Jin, Zhengshi Wang, Xianjun Yu, Chen Liu
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s00262-018-2235-8) contains supplementary material, which is available to authorized users.
Chao Yang and He Cheng contributed equally to this work.
The work was published as a poster at the 50th Jubilee Meeting of the European Pancreatic Club (EPC2018), 13–16 June 2018, in Berlin, Germany [1].



Natural killer cells (NK) are often believed to play a positive role in the antitumor immune response. However, this is not the case for patients with advanced pancreatic cancer. This study was performed to determine the unique subtype of “educated” NK cells and their prognostic value in patients with advanced pancreatic cancer.


We divided 378 eligible patients into a derivation cohort (September 2010 to December 2014, n = 239) and a validation cohort (January 2015 to April 2016, n = 139). Flow cytometry was performed to analyze NK cells. Enzyme-linked immunosorbent assay was used to detect interleukin-2 (IL-2), interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) production. The Kaplan–Meier method and the Cox proportional hazards model were used.


Survival analysis showed that a high density of NK cells accompanied by a high neutrophil-to-lymphocyte ratio was associated with reduced overall survival in both the derivation and validation cohorts. Multivariable analysis also showed that high NK infiltration (HR 1.45, 95% CI 1.17 to 1.79, p = 0.001) was an independent prognostic factor. In these patients, high NK infiltration was associated with reduced levels of IL-2, IFN-γ and TNF-α, although only IFN-γ reached statistical significance, which accounted for this unique phenomenon.


Natural killer cells in patients with advanced pancreatic cancer are a unique subtype with anergic features. A high density of NKs predicts poor survival in these patients, possibly because an active inflammatory response and reduced secretion of IL-2, IFN-γ and TNF-α inhibit NK activation.

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