Original Article

Cancer Immunology, Immunotherapy

, Volume 63, Issue 6, pp 571-580

First online:

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

  • Manuela Frese-SchaperAffiliated withDepartment of Clinical Research, University of BernDivision of General Thoracic Surgery, University Hospital Bern
  • , Andreas KeilAffiliated withDepartment of Clinical Research, University of BernDivision of General Thoracic Surgery, University Hospital Bern
  • , Hideo YagitaAffiliated withDepartment of Immunology, Juntendo University School of Medicine
  • , Selina Katja SteinerAffiliated withDepartment of Clinical Research, University of BernDivision of General Thoracic Surgery, University Hospital Bern
  • , Werner FalkAffiliated withDepartment of Internal Medicine I, University of Regensburg
  • , Ralph Alexander SchmidAffiliated withDivision of General Thoracic Surgery, University Hospital Bern
  • , Steffen FreseAffiliated withDepartment of Clinical Research, University of BernDivision of General Thoracic Surgery, University Hospital Bern Email author 

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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.

Keywords

Lung cancer Natural killer cells Perforin-mediated cytolysis Tumour necrosis factors Apoptosis Immunogenicity