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Cigarette Smoke Impairs NK Cell-Dependent Tumor Immune Surveillance¹

Ling-Min Lu^2,*, Caleb C. J. Zavitz^*, Biao Chen^*, Sussan Kianpour^*, Yonghong Wan^* and Martin R. Stämpfli^3,*,

^* Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics and Department of Medicine, McMaster University, Hamilton, Ontario, Canada

In this study, we investigated the impact of cigarette smoke on tumor immune surveillance and its consequences to lung tumor burden in a murine lung metastasis model. Cigarette smoke exposure significantly increased the numbers of lung metastases following B16-MO5 melanoma challenge. This effect was reversible; we observed significantly fewer tumor nodules following smoking cessation. Using RAG2^–/– and RAG2^–/–_c^–/– mice, we provide strong evidence that increased tumor incidence was NK cell dependent. Furthermore, we show that cigarette smoke suppressed NK activation and attenuated NK CTL activity, without apparent effect on activating or inhibitory receptor expression. Finally, activation of NK cells through bone marrow-derived dendritic cells conferred protection against lung metastases in smoke-exposed mice; however, protection was not as efficacious as in sham-exposed mice. To our knowledge, this is the first experimental evidence showing that cigarette smoke impairs NK cell-dependent tumor immune surveillance and that altered immunity is associated with increased tumor burden. Our findings suggest that altered innate immunity may contribute to the increased risk of cancer in smokers.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Philip Morris USA and Philip Morris International and the Canadian Institutes of Health Research (CIHR). M.R.S. is holder of a CIHR New Investigator Award.

² Current address: Department of Respiratory and Rheumatology Pharmacology, Sanofi-Aventis Pharmaceutical, Bridgewater, NJ.

³ Address correspondence and reprint requests to Dr. Martin R. Stämpfli, Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote Center for Learning and Discovery, Room 4011, 1200 Main Street West, Hamilton, Ontario, Canada. E-mail address: stampfli{at}mcmaster.ca

⁴ Abbreviations used in this paper: COHb, carboxyhemoglobin; 7-AAD, 7-aminoactinomycin D.

This article has been cited by other articles:

				M. F. Mian, N. M. Lauzon, M. R. Stampfli, K. L. Mossman, and A. A. Ashkar Impairment of human NK cell cytotoxic activity and cytokine release by cigarette smoke J. Leukoc. Biol., March 1, 2008; 83(3): 774 - 784. [Abstract] [Full Text] [PDF]