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Influence of natural killer cells and perforin-mediated cytolysis on the development of chemically induced lung cancer in A/J mice

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Abstract

One alternative approach for the treatment of lung cancer might be the activation of the immune system using vaccination strategies. However, most of clinical vaccination trials for lung cancer did not reach their primary end points, suggesting that lung cancer is of low immunogenicity. To provide additional experimental information about this important issue, we investigated which type of immune cells contributes to the protection from lung cancer development. Therefore, A/J mice induced for lung adenomas/adenocarcinomas by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were depleted of CD4+ or CD8+ T cells, CD11b+ macrophages, Gr-1+ neutrophils and asialo GM1+ natural killer (NK) cells. Subsequent analysis of tumour growth showed an increase in tumour number only in mice depleted of NK cells. Further asking by which mechanism NK cells suppressed tumour development, we neutralized several death ligands of the tumour necrosis factor (TNF) family known to be involved in NK cell-mediated cytotoxicity. However, neither depletion of TNF-α, TNF-related apoptosis-inducing ligand, TNF-like weak inducer of apoptosis or FasL alone nor in combination induced an augmentation of tumour burden. To show whether an alternative cell death pathway is involved, we next generated A/J mice deficient for perforin. After challenging with NNK, mice deficient for perforin showed an increase in tumour number and volume compared to wild-type A/J mice. In summary, our data suggest that NK cells and perforin-mediated cytolysis are critically involved in the protection from lung cancer giving promise for further immunotherapeutic strategies for this disease.

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Abbreviations

NSCLC:

Non-small cell lung cancer

NNK:

Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

NK:

Natural killer

TNF:

Tumor necrosis factor

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

TWEAK:

TNF-like weak inducer of apoptosis

PKO:

Perforin-deficiency

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Acknowledgments

We thank Beatrice Zumkehr for technical assistance. We are also thankful to Hans Hengartner for providing a breeding pair of PKO mice on a C57BL/6 background. This work was supported by the Bernische Krebsliga and by the Stiftung für Klinisch-Experimentelle Krebsforschung Bern, both grants to Steffen Frese.

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Authors and Affiliations

  1. Department of Clinical Research, University of Bern, Murtenstrasse 50, P.O. Box 44, 3010, Bern, Switzerland

    Manuela Frese-Schaper, Andreas Keil, Selina Katja Steiner & Steffen Frese

  2. Department of Immunology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan

    Hideo Yagita

  3. Department of Internal Medicine I, University of Regensburg, 93042, Regensburg, Germany

    Werner Falk

  4. Division of General Thoracic Surgery, University Hospital Bern, 3010, Bern, Switzerland

    Manuela Frese-Schaper, Andreas Keil, Selina Katja Steiner, Ralph Alexander Schmid & Steffen Frese

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  1. Manuela Frese-Schaper
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  2. Andreas Keil
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  3. Hideo Yagita
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  4. Selina Katja Steiner
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  7. Steffen Frese
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Correspondence to Steffen Frese.

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Frese-Schaper, M., Keil, A., Yagita, H. et al. Influence of natural killer cells and perforin-mediated cytolysis on the development of chemically induced lung cancer in A/J mice. Cancer Immunol Immunother 63, 571–580 (2014). https://doi.org/10.1007/s00262-014-1535-x

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