Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Introduction

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.

Methods

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.

Results

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.

Discussion

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

CBC:

Complete blood counts

CI:

Confidence interval

FDUSCC:

Fudan University Shanghai Cancer Center

HIS:

Hospital Information System

HR:

Hazard ratio

MMP:

Matrix metalloproteinase

NCAM:

Neural cell adhesion molecule

NLR:

Neutrophil-to-lymphocyte ratio

PDAC:

Pancreatic ductal adenocarcinoma

TRF2:

Telomeric repeat binding factor 2

References

  1. Yang C, Liu C, Yu X (2018) Anergic natural killer cells educated by tumor cells are associated with poor prognosis in patients with advanced pancreatic ductal adenocarcinoma. Pancreatology 18(4 Supplement):S134 (poster number: P3–104)

    Article  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7–30

    Article  Google Scholar 

  3. Xu YF, Lu Y, Cheng H, Shi S, Xu J, Long J, Liu L, Liu C, Yu X (2014) Abnormal distribution of peripheral lymphocyte subsets induced by PDAC modulates overall survival. Pancreatology 14:295–301

    Article  CAS  Google Scholar 

  4. Platonova S, Cherfils-Vicini J, Damotte D, Crozet L, Vieillard V, Validire P, Andre P, Dieu-Nosjean MC, Alifano M, Regnard JF, Fridman WH, Sautes-Fridman C, Cremer I (2011) Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res 71:5412–5422

    Article  CAS  Google Scholar 

  5. Fehniger TA, Cooper MA, Nuovo GJ, Cella M, Facchetti F, Colonna M, Caligiuri MA (2003) CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood 101:3052–3057

    Article  CAS  Google Scholar 

  6. Costanzo MC, Creegan M, Lal KG, Eller MA (2015) OMIP-027: functional analysis of human natural killer cells. Cytometry A 87:803–805

    Article  Google Scholar 

  7. Bhatti I, Peacock O, Lloyd G, Larvin M, Hall RI (2010) Preoperative hematologic markers as independent predictors of prognosis in resected pancreatic ductal adenocarcinoma: neutrophil–lymphocyte versus platelet–lymphocyte ratio. Am J Surg 200:197–203

    Article  Google Scholar 

  8. Garcea G, Ladwa N, Neal CP, Metcalfe MS, Dennison AR, Berry DP (2011) Preoperative neutrophil-to-lymphocyte ratio (NLR) is associated with reduced disease-free survival following curative resection of pancreatic adenocarcinoma. World J Surg 35:868–872

    Article  CAS  Google Scholar 

  9. Luo G, Guo M, Liu Z, Xiao Z, Jin K, Long J, Liu L, Liu C, Xu J, Ni Q, Yu X (2015) Blood neutrophil–lymphocyte ratio predicts survival in patients with advanced pancreatic cancer treated with chemotherapy. Ann Surg Oncol 22:670–676

    Article  Google Scholar 

  10. Kuzman JA, Stenehjem DD, Merriman J, Agarwal AM, Patel SB, Hahn AW, Alex A, Albertson D, Gill DM, Agarwal N (2017) Neutrophil–lymphocyte ratio as a predictive biomarker for response to high dose interleukin-2 in patients with renal cell carcinoma. BMC Urol 17:1

    Article  Google Scholar 

  11. Foley K, Kim V, Jaffee E, Zheng L (2016) Current progress in immunotherapy for pancreatic cancer. Cancer Lett 381:244–251

    Article  CAS  Google Scholar 

  12. Stotz M, Gerger A, Eisner F, Szkandera J, Loibner H, Ress AL, Kornprat P, AlZoughbi W, Seggewies FS, Lackner C, Stojakovic T, Samonigg H, Hoefler G, Pichler M (2013) Increased neutrophil–lymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer. Br J Cancer 109:416–421

    Article  CAS  Google Scholar 

  13. Ben Q, An W, Wang L, Wang W, Yu L, Yuan Y (2015) Validation of the pretreatment neutrophil–lymphocyte ratio as a predictor of overall survival in a cohort of patients with pancreatic ductal adenocarcinoma. Pancreas 44:471–477

    CAS  PubMed  Google Scholar 

  14. Balsamo M, Scordamaglia F, Pietra G, Manzini C, Cantoni C, Boitano M, Queirolo P, Vermi W, Facchetti F, Moretta A, Moretta L, Mingari MC, Vitale M (2009) Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. Proc Natl Acad Sci USA 106:20847–20852

    Article  CAS  Google Scholar 

  15. Kerdiles Y, Ugolini S, Vivier E (2013) T cell regulation of natural killer cells. J Exp Med 210:1065–1068

    Article  CAS  Google Scholar 

  16. Kundig TM, Schorle H, Bachmann MF, Hengartner H, Zinkernagel RM, Horak I (1993) Immune responses in interleukin-2-deficient mice. Science 262:1059–1061

    Article  CAS  Google Scholar 

  17. Horowitz A, Hafalla JC, King E, Lusingu J, Dekker D, Leach A, Moris P, Cohen J, Vekemans J, Villafana T, Corran PH, Bejon P, Drakeley CJ, von Seidlein L, Riley EM (2012) Antigen-specific IL-2 secretion correlates with NK cell responses after immunization of Tanzanian children with the RTS,S/AS01 malaria vaccine. J Immunol 188:5054–5062

    Article  CAS  Google Scholar 

  18. Boyman O, Sprent J (2012) The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol 12:180–190

    Article  CAS  Google Scholar 

  19. Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V, Sene D, Cacoub P, Klatzmann D (2011) Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med 365:2067–2077

    Article  CAS  Google Scholar 

  20. Boyman O, Kovar M, Rubinstein MP, Surh CD, Sprent J (2006) Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311:1924–1927

    Article  CAS  Google Scholar 

  21. Lee BK, Kim MJ, Jang HS, Lee HR, Ahn KM, Lee JH, Choung PH, Kim MJ (2008) A high concentration of MMP-2/gelatinase A and MMP-9/gelatinase B reduce NK cell-mediated cytotoxicity against an oral squamous cell carcinoma cell line. In Vivo 22:593–597

    CAS  PubMed  Google Scholar 

  22. Pesce S, Greppi M, Tabellini G, Rampinelli F, Parolini S, Olive D, Moretta L, Moretta A, Marcenaro E (2017) Identification of a subset of human natural killer cells expressing high levels of programmed death 1: a phenotypic and functional characterization. J Allergy Clin Immunol 139:335–346

    Article  CAS  Google Scholar 

  23. Ndhlovu LC, Lopez-Verges S, Barbour JD, Jones RB, Jha AR, Long BR, Schoeffler EC, Fujita T, Nixon DF, Lanier LL (2012) Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood 119:3734–3743

    Article  CAS  Google Scholar 

  24. Gonzalez-Gugel E, Saxena M, Bhardwaj N (2016) Modulation of innate immunity in the tumor microenvironment. Cancer Immunol Immunother 65:1261–1268

    Article  CAS  Google Scholar 

  25. Carrega P, Morandi B, Costa R, Frumento G, Forte G, Altavilla G, Ratto GB, Mingari MC, Moretta L, Ferlazzo G (2008) Natural killer cells infiltrating human nonsmall-cell lung cancer are enriched in CD56 bright CD16(−) cells and display an impaired capability to kill tumor cells. Cancer 112:863–875

    Article  Google Scholar 

  26. Le Maux CB, Moretta A, Vergnon I, Opolon P, Lecluse Y, Grunenwald D, Kubin M, Soria JC, Chouaib S, Mami-Chouaib F (2005) NK cells infiltrating a MHC class I-deficient lung adenocarcinoma display impaired cytotoxic activity toward autologous tumor cells associated with altered NK cell-triggering receptors. J Immunol 175:5790–5798

    Article  Google Scholar 

  27. Bix M, Liao NS, Zijlstra M, Loring J, Jaenisch R, Raulet D (1991) Rejection of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice. Nature 349:329–331

    Article  CAS  Google Scholar 

  28. Gurlevik E, Fleischmann-Mundt B, Brooks J, Demir IE, Steiger K, Ribback S, Yevsa T, Woller N, Kloos A, Ostroumov D, Armbrecht N, Manns MP, Dombrowski F, Saborowski M, Kleine M, Wirth TC, Oettle H, Ceyhan GO, Esposito I, Calvisi DF, Kubicka S, Kuhnel F (2016) Administration of gemcitabine after pancreatic tumor resection in mice induces an antitumor immune response mediated by natural killer cells. Gastroenterology 151:338–350

    Article  Google Scholar 

  29. Plate JM, Plate AE, Shott S, Bograd S, Harris JE (2005) Effect of gemcitabine on immune cells in subjects with adenocarcinoma of the pancreas. Cancer Immunol Immunother 54:915–925

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by National Natural Science Foundation of China Grants (81370065, 81372653), a basic research project of the Science and Technology Commission of Shanghai Municipality (15JC1401200), and the National Science Fund for Distinguished Young Scholars (81625016).

Author information

Author notes

  1. Chao Yang and He Cheng contributed equally to this work.

Authors and Affiliations

  1. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Xuhui District, Shanghai, 200032, People’s Republic of China

    Chao Yang, He Cheng, Yiyin Zhang, Kun Fan, Guopei Luo, Zhiyao Fan, Qiuyi Huang, Yu Lu, Kaizhou Jin, Zhengshi Wang, Xianjun Yu & Chen Liu

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China

    Chao Yang, He Cheng, Yiyin Zhang, Kun Fan, Guopei Luo, Zhiyao Fan, Qiuyi Huang, Yu Lu, Kaizhou Jin, Zhengshi Wang, Xianjun Yu & Chen Liu

  3. Shanghai Pancreatic Cancer Institute, Shanghai, 200032, People’s Republic of China

    Chao Yang, He Cheng, Yiyin Zhang, Kun Fan, Guopei Luo, Zhiyao Fan, Qiuyi Huang, Yu Lu, Kaizhou Jin, Zhengshi Wang, Xianjun Yu & Chen Liu

  4. Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, People’s Republic of China

    Chao Yang, He Cheng, Yiyin Zhang, Kun Fan, Guopei Luo, Zhiyao Fan, Qiuyi Huang, Yu Lu, Kaizhou Jin, Zhengshi Wang, Xianjun Yu & Chen Liu

Authors
  1. Chao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. He Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yiyin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kun Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guopei Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhiyao Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qiuyi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yu Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kaizhou Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhengshi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xianjun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Chen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CY, HC, CL and XY were involved in the study conception and design. CY and HC were involved in the acquisition, analysis, and interpretation of the data. CY drafted the manuscript, and all authors were involved in critical revision of the manuscript.

Corresponding authors

Correspondence to Xianjun Yu or Chen Liu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest to disclose.

Ethical approval and ethical standards

The study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (FDUSCC) and met ethical guidelines of the World Medical Association Declaration of Helsinki. Written informed consent was acquired at FDUSCC.

Additional information

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].

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 351 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, C., Cheng, H., Zhang, Y. et al. Anergic natural killer cells educated by tumor cells are associated with a poor prognosis in patients with advanced pancreatic ductal adenocarcinoma. Cancer Immunol Immunother 67, 1815–1823 (2018). https://doi.org/10.1007/s00262-018-2235-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-018-2235-8

Keywords

Search

Navigation