Cigarette smoke impairs NK cell-dependent tumor immune surveillance.
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(-/-)gamma(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.
Lu
Ling-Min
LM
Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada.
Zavitz
Caleb C J
CC
Chen
Biao
B
Kianpour
Sussan
S
Wan
Yonghong
Y
Stämpfli
Martin R
MR
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D007157:Immunologic Surveillance / Q000187:drug effects / Q000276:immunology*; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D037181:Lectins, C-Type; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D012906:Smoke / Q000009:adverse effects*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014026:Nicotiana / Q000009:adverse effects*; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D004268:DNA-Binding Proteins; D018664:Interleukin-12; D037181:Lectins, C-Type; D012906:Smoke; D000099192:CD69 Antigens; C499308:Rag2 protein, mouse