@article{3000655,
    title = "Cigarette smoke-induced emphysema exhausts early cytotoxic CD8 + T cell responses against nascent lung cancer cells",
    author = "Kerdidani, D. and Magkouta, S. and Chouvardas, P. and Karavana, V. and Glynos, K. and Roumelioti, F. and Zakynthinos, S. and Wauters, E. and Janssens, W. and Lambrechts, D. and Kollias, G. and Tsoumakidou, M.",
    journal = "Journal of Immunological Methods",
    year = "2018",
    volume = "201",
    number = "5",
    pages = "1558-1569",
    publisher = "American Association of Immunologists",
    issn = "0022-1759",
    doi = "10.4049/jimmunol.1700700",
    keywords = "glycoprotein p 15095;  major histocompatibility antigen class 2;  programmed death 1 ligand 1, adoptive transfer;  animal cell;  animal experiment;  animal model;  animal tissue;  Article;  cancer inhibition;  CD8+ T lymphocyte;  cell expansion;  cell function;  cell infiltration;  cell selection;  cellular immunity;  cigarette smoke-induced emphysema;  cytotoxic T lymphocyte;  down regulation;  immunocompetence;  immunoregulation;  lung cancer;  lymphocyte activation;  lymphocyte transfer;  mouse;  mouse model;  myeloid dendritic cell;  nonhuman;  oxidative stress;  priority journal;  protein expression;  tumor microenvironment;  upregulation;  animal;  CD8+ T lymphocyte;  cigarette smoking;  immunology;  lung emphysema;  lung tumor;  pathology;  pathophysiology;  transgenic mouse;  transplantation, Adoptive Transfer;  Animals;  CD8-Positive T-Lymphocytes;  Cigarette Smoking;  Lung Neoplasms;  Mice;  Mice, Transgenic;  Pulmonary Emphysema",
    abstract = "Chronic obstructive pulmonary disease is a chronic inflammatory disorder with an increased incidence of lung cancer. The emphysema component of chronic obstructive pulmonary disease confers the greatest proportion to lung cancer risk. Although tumors create inflammatory conditions to escape immunity, the immunological responses that control growth of nascent cancer cells in pre-established inflammatory microenvironments are unknown. In this study, we addressed this issue by implanting OVA-expressing cancer cells in the lungs of mice with cigarette smoke-induced emphysema. Emphysema augmented the growth of cancer cells, an effect that was dependent on T cytotoxic cells. OVA-specific OTI T cells showed early signs of exhaustion upon transfer in emphysema tumor hosts that was largely irreversible because sorting, expansion, and adoptive transfer failed to restore their antitumor activity. Increased numbers of PD-L1- and IDO-positive CD11c+ myeloid dendritic cells (DCs) infiltrated emphysema tumors, whereas sorted emphysema tumor DCs poorly stimulated OTI T cells. Upon adoptive transfer in immunocompetent hosts, T cells primed by emphysema tumor DCs were unable to halt tumor growth. DCs exposed to the emphysema tumor microenvironment downregulated MHC class II and costimulatory molecules, whereas they upregulated PD-L1/IDO via oxidative stress-dependent mechanisms. T cell activation increased upon PD-L1 blockade in emphysema DC-T cell cocultures and in emphysema tumor hosts in vivo. Analysis of the transcriptome of primary human lung tumors showed a strong association between computed tomography-based emphysema scoring and downregulation of immunogenic processes. Thus, suppression of adaptive immunity against lung cancer cells links a chronic inflammatory disorder, emphysema, to cancer, with clinical implications for emphysema patients to be considered optimal candidates for cancer immunotherapies. © 2018 by The American Association of Immunologists, Inc."
}