Cancer Immunology, Immunotherapy

, Volume 63, Issue 6, pp 571–580 | Cite as

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

  • Manuela Frese-Schaper
  • Andreas Keil
  • Hideo Yagita
  • Selina Katja Steiner
  • Werner Falk
  • Ralph Alexander Schmid
  • Steffen Frese
Original Article

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 

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

Notes

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.

Conflict of interest

None.

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. doi: 10.3322/caac.20107 PubMedCrossRefGoogle Scholar
  2. 2.
    Midthun DE, Jett JR (2008) Lung tumors. In: Albert RK, Spiro SG, Jett JR (eds) Clinical respiratory medicine, 3rd edn. Mosby Elsevier, Philadelphia, p 605–632Google Scholar
  3. 3.
    Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF, Investigators IS (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363(5):411–422. doi: 10.1056/NEJMoa1001294 PubMedCrossRefGoogle Scholar
  4. 4.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723. doi: 10.1056/NEJMoa1003466 PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Rioux N, Castonguay A (1997) Recovery from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced immunosuppression in A/J mice by treatment with nonsteroidal anti-inflammatory drugs. J Natl Cancer Inst 89(12):874–880PubMedCrossRefGoogle Scholar
  6. 6.
    Holt PG (1987) Immune and inflammatory function in cigarette smokers. Thorax 42(4):241–249PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Gure AO, Chua R, Williamson B, Gonen M, Ferrera CA, Gnjatic S, Ritter G, Simpson AJ, Chen YT, Old LJ, Altorki NK (2005) Cancer-testis genes are coordinately expressed and are markers of poor outcome in non-small cell lung cancer. Clin Cancer Res 11(22):8055–8062. doi: 10.1158/1078-0432.CCR-05-1203 PubMedCrossRefGoogle Scholar
  8. 8.
    Guddo F, Giatromanolaki A, Koukourakis MI, Reina C, Vignola AM, Chlouverakis G, Hilkens J, Gatter KC, Harris AL, Bonsignore G (1998) MUC1 (episialin) expression in non-small cell lung cancer is independent of EGFR and c-erbB-2 expression and correlates with poor survival in node positive patients. J Clin Pathol 51(9):667–671PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Tyagi P, Mirakhur B (2009) MAGRIT: the largest-ever phase III lung cancer trial aims to establish a novel tumor-specific approach to therapy. Clin Lung Cancer 10(5):371–374. doi: 10.3816/CLC.2009.n.052 PubMedCrossRefGoogle Scholar
  10. 10.
    Butts C, Murray N, Maksymiuk A, Goss G, Marshall E, Soulieres D, Cormier Y, Ellis P, Price A, Sawhney R, Davis M, Mansi J, Smith C, Vergidis D, Ellis P, MacNeil M, Palmer M (2005) Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol 23(27):6674–6681. doi: 10.1200/JCO.2005.13.011 PubMedCrossRefGoogle Scholar
  11. 11.
    Nemunaitis J, Dillman RO, Schwarzenberger PO, Senzer N, Cunningham C, Cutler J, Tong A, Kumar P, Pappen B, Hamilton C, DeVol E, Maples PB, Liu L, Chamberlin T, Shawler DL, Fakhrai H (2006) Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol 24(29):4721–4730. doi: 10.1200/JCO.2005.05.5335 PubMedCrossRefGoogle Scholar
  12. 12.
    Hecht SS, Morse MA, Amin S, Stoner GD, Jordan KG, Choi CI, Chung FL (1989) Rapid single-dose model for lung tumor induction in A/J mice by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and the effect of diet. Carcinogenesis 10(10):1901–1904PubMedCrossRefGoogle Scholar
  13. 13.
    Belinsky SA, Stefanski SA, Anderson MW (1993) The A/J mouse lung as a model for developing new chemointervention strategies. Cancer Res 53(2):410–416PubMedGoogle Scholar
  14. 14.
    Hecht SS (1995) Chemoprevention by isothiocyanates. J Cell Biochem Suppl 22:195–209PubMedCrossRefGoogle Scholar
  15. 15.
    Takeuchi H, Saoo K, Yokohira M, Ikeda M, Maeta H, Miyazaki M, Yamazaki H, Kamataki T, Imaida K (2003) Pretreatment with 8-methoxypsoralen, a potent human CYP2A6 inhibitor, strongly inhibits lung tumorigenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in female A/J mice. Cancer Res 63(22):7581–7583PubMedGoogle Scholar
  16. 16.
    Lantry LE, Zhang Z, Yao R, Crist KA, Wang Y, Ohkanda J, Hamilton AD, Sebti SM, Lubet RA, You M (2000) Effect of farnesyltransferase inhibitor FTI-276 on established lung adenomas from A/J mice induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Carcinogenesis 21(1):113–116PubMedCrossRefGoogle Scholar
  17. 17.
    Belinsky SA, Devereux TR, Maronpot RR, Stoner GD, Anderson MW (1989) Relationship between the formation of promutagenic adducts and the activation of the K-ras protooncogene in lung tumors from A/J mice treated with nitrosamines. Cancer Res 49(19):5305–5311PubMedGoogle Scholar
  18. 18.
    Matzinger SA, Crist KA, Stoner GD, Anderson MW, Pereira MA, Steele VE, Kelloff GJ, Lubet RA, You M (1995) K-ras mutations in lung tumors from A/J and A/J x TSG-p53 F1 mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and phenethyl isothiocyanate. Carcinogenesis 16(10):2487–2492PubMedCrossRefGoogle Scholar
  19. 19.
    Whyte AL, Miller SC (1998) Strain differences in natural killer cell-mediated immunity among mice: a possible mechanism for the low natural killer cell activity of A/J mice. Immunobiology 199(1):23–38. doi: 10.1016/S0171-2985(98)80061-2 PubMedCrossRefGoogle Scholar
  20. 20.
    Kreisel D, Gelman AE, Higashikubo R, Lin X, Vikis HG, White JM, Toth KA, Deshpande C, Carreno BM, You M, Taffner SM, Yokoyama WM, Bui JD, Schreiber RD, Krupnick AS (2012) Strain-specific variation in murine natural killer gene complex contributes to differences in immunosurveillance for urethane-induced lung cancer. Cancer Res 72(17):4311–4317. doi: 10.1158/0008-5472.CAN-12-0908 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Pepin P, Bouchard L, Nicole P, Castonguay A (1992) Effects of sulindac and oltipraz on the tumorigenicity of 4-(methylnitrosamino)1-(3-pyridyl)-1-butanone in A/J mouse lung. Carcinogenesis 13(3):341–348PubMedCrossRefGoogle Scholar
  22. 22.
    Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450(7171):903–907. doi: 10.1038/nature06309 PubMedCrossRefGoogle Scholar
  23. 23.
    Crowe NY, Smyth MJ, Godfrey DI (2002) A critical role for natural killer T cells in immunosurveillance of methylcholanthrene-induced sarcomas. J Exp Med 196(1):119–127PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Stagg J, Sharkey J, Pommey S, Young R, Takeda K, Yagita H, Johnstone RW, Smyth MJ (2008) Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response. Proc Natl Acad Sci USA 105(42):16254–16259. doi: 10.1073/pnas.0806849105 PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Takeda K, Yamaguchi N, Akiba H, Kojima Y, Hayakawa Y, Tanner JE, Sayers TJ, Seki N, Okumura K, Yagita H, Smyth MJ (2004) Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy. J Exp Med 199(4):437–448. doi: 10.1084/jem.20031457 PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Hong F, Hansen RD, Yan J, Allendorf DJ, Baran JT, Ostroff GR, Ross GD (2003) Beta-glucan functions as an adjuvant for monoclonal antibody immunotherapy by recruiting tumoricidal granulocytes as killer cells. Cancer Res 63(24):9023–9031PubMedGoogle Scholar
  27. 27.
    Kayagaki N, Yamaguchi N, Nakayama M, Takeda K, Akiba H, Tsutsui H, Okamura H, Nakanishi K, Okumura K, Yagita H (1999) Expression and function of TNF-related apoptosis-inducing ligand on murine activated NK cells. J Immunol 163(4):1906–1913PubMedGoogle Scholar
  28. 28.
    Nakayama M, Harada N, Okumura K, Yagita H (2003) Characterization of murine TWEAK and its receptor (Fn14) by monoclonal antibodies. Biochem Biophys Res Commun 306(4):819–825PubMedCrossRefGoogle Scholar
  29. 29.
    Kayagaki N, Yamaguchi N, Nagao F, Matsuo S, Maeda H, Okumura K, Yagita H (1997) Polymorphism of murine Fas ligand that affects the biological activity. Proc Natl Acad Sci USA 94(8):3914–3919PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Echtenacher B, Falk W, Mannel DN, Krammer PH (1990) Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis. J Immunol 145(11):3762–3766PubMedGoogle Scholar
  31. 31.
    Kagi D, Ledermann B, Burki K, Seiler P, Odermatt B, Olsen KJ, Podack ER, Zinkernagel RM, Hengartner H (1994) Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369(6475):31–37. doi: 10.1038/369031a0 PubMedCrossRefGoogle Scholar
  32. 32.
    Kagi D, Odermatt B, Seiler P, Zinkernagel RM, Mak TW, Hengartner H (1997) Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice. J Exp Med 186(7):989–997PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Frese-Schaper M, Zbaeren J, Gugger M, Monestier M, Frese S (2010) Reversal of established lupus nephritis and prolonged survival of New Zealand black × New Zealand white mice treated with the topoisomerase I inhibitor irinotecan. J Immunol 184(4):2175–2182. doi: 10.4049/jimmunol.0903153 PubMedCrossRefGoogle Scholar
  34. 34.
    Smyth MJ, Hayakawa Y, Takeda K, Yagita H (2002) New aspects of natural-killer-cell surveillance and therapy of cancer. Nat Rev Cancer 2(11):850–861. doi: 10.1038/nrc928 PubMedCrossRefGoogle Scholar
  35. 35.
    Voskoboinik I, Dunstone MA, Baran K, Whisstock JC, Trapani JA (2010) Perforin: structure, function, and role in human immunopathology. Immunol Rev 235(1):35–54. doi: 10.1111/j.0105-2896.2010.00896.x PubMedGoogle Scholar
  36. 36.
    Granville CA, Memmott RM, Balogh A, Mariotti J, Kawabata S, Han W, Lopiccolo J, Foley J, Liewehr DJ, Steinberg SM, Fowler DH, Hollander MC, Dennis PA (2009) A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis. PLoS One 4(3):e5061. doi: 10.1371/journal.pone.0005061 PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Karre K, Ljunggren HG, Piontek G, Kiessling R (1986) Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319(6055):675–678. doi: 10.1038/319675a0 PubMedCrossRefGoogle Scholar
  38. 38.
    Smyth MJ, Crowe NY, Godfrey DI (2001) NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int Immunol 13(4):459–463PubMedCrossRefGoogle Scholar
  39. 39.
    Uchida A, Colot M, Micksche M (1984) Suppression of natural killer cell activity by adherent effusion cells of cancer patients. Suppression of motility, binding capacity and lethal hit of NK cells. Br J Cancer 49(1):17–23PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    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(16):5412–5422. doi: 10.1158/0008-5472.CAN-10-4179 PubMedCrossRefGoogle Scholar
  41. 41.
    Cretney E, Takeda K, Yagita H, Glaccum M, Peschon JJ, Smyth MJ (2002) Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 168(3):1356–1361PubMedCrossRefGoogle Scholar
  42. 42.
    Roths JB, Murphy ED, Eicher EM (1984) A new mutation, gld, that produces lymphoproliferation and autoimmunity in C3H/HeJ mice. J Exp Med 159(1):1–20PubMedCrossRefGoogle Scholar
  43. 43.
    Takeda K, Smyth MJ, Cretney E, Hayakawa Y, Kayagaki N, Yagita H, Okumura K (2002) Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med 195(2):161–169PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Moore RJ, Owens DM, Stamp G, Arnott C, Burke F, East N, Holdsworth H, Turner L, Rollins B, Pasparakis M, Kollias G, Balkwill F (1999) Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 5(7):828–831. doi: 10.1038/10552 PubMedCrossRefGoogle Scholar
  45. 45.
    Scott KA, Moore RJ, Arnott CH, East N, Thompson RG, Scallon BJ, Shealy DJ, Balkwill FR (2003) An anti-tumor necrosis factor-alpha antibody inhibits the development of experimental skin tumors. Mol Cancer Ther 2(5):445–451PubMedGoogle Scholar
  46. 46.
    Ho DH, Vu H, Brown SA, Donohue PJ, Hanscom HN, Winkles JA (2004) Soluble tumor necrosis factor-like weak inducer of apoptosis overexpression in HEK293 cells promotes tumor growth and angiogenesis in athymic nude mice. Cancer Res 64(24):8968–8972. doi: 10.1158/0008-5472.CAN-04-1879 PubMedCrossRefGoogle Scholar
  47. 47.
    Frese S, Frese-Schaper M, Andres AC, Miescher D, Zumkehr B, Schmid RA (2006) Cardiac glycosides initiate Apo2L/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulation of death receptors 4 and 5. Cancer Res 66(11):5867–5874. doi: 10.1158/0008-5472.CAN-05-3544 PubMedCrossRefGoogle Scholar
  48. 48.
    Frese-Schaper M, Schardt JA, Sakai T, Carboni GL, Schmid RA, Frese S (2010) Inhibition of tissue transglutaminase sensitizes TRAIL-resistant lung cancer cells through upregulation of death receptor 5. FEBS Lett 584(13):2867–2871. doi: 10.1016/j.febslet.2010.04.072 PubMedCrossRefGoogle Scholar
  49. 49.
    Smyth MJ, Johnstone RW, Cretney E, Haynes NM, Sedgwick JD, Korner H, Poulton LD, Baxter AG (1999) Multiple deficiencies underlie NK cell inactivity in lymphotoxin-alpha gene-targeted mice. J Immunol 163(3):1350–1353PubMedGoogle Scholar
  50. 50.
    Street SE, Cretney E, Smyth MJ (2001) Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. Blood 97(1):192–197PubMedCrossRefGoogle Scholar
  51. 51.
    Smyth MJ, Crowe NY, Pellicci DG, Kyparissoudis K, Kelly JM, Takeda K, Yagita H, Godfrey DI (2002) Sequential production of interferon-gamma by NK1.1(+) T cells and natural killer cells is essential for the antimetastatic effect of alpha-galactosylceramide. Blood 99(4):1259–1266PubMedCrossRefGoogle Scholar
  52. 52.
    Giaccone G, Punt CJ, Ando Y, Ruijter R, Nishi N, Peters M, von Blomberg BM, Scheper RJ, van der Vliet HJ, van den Eertwegh AJ, Roelvink M, Beijnen J, Zwierzina H, Pinedo HM (2002) A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res 8(12):3702–3709PubMedGoogle Scholar
  53. 53.
    Motohashi S, Nagato K, Kunii N, Yamamoto H, Yamasaki K, Okita K, Hanaoka H, Shimizu N, Suzuki M, Yoshino I, Taniguchi M, Fujisawa T, Nakayama T (2009) A phase I-II study of alpha-galactosylceramide-pulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer. J Immunol 182(4):2492–2501. doi: 10.4049/jimmunol.0800126 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Manuela Frese-Schaper
    • 1
    • 4
  • Andreas Keil
    • 1
    • 4
  • Hideo Yagita
    • 2
  • Selina Katja Steiner
    • 1
    • 4
  • Werner Falk
    • 3
  • Ralph Alexander Schmid
    • 4
  • Steffen Frese
    • 1
    • 4
  1. 1.Department of Clinical ResearchUniversity of BernBernSwitzerland
  2. 2.Department of ImmunologyJuntendo University School of MedicineTokyoJapan
  3. 3.Department of Internal Medicine IUniversity of RegensburgRegensburgGermany
  4. 4.Division of General Thoracic SurgeryUniversity Hospital BernBernSwitzerland

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