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A dual role for the immune response in a mouse model of inflammation-associated lung cancer.

ABSTRACT: Lung cancer is the leading cause of cancer death worldwide. Both principal factors known to cause lung cancer, cigarette smoke and asbestos, induce pulmonary inflammation, and pulmonary inflammation has recently been implicated in several murine models of lung cancer. To further investigate the role of inflammation in the development of lung cancer, we generated mice with combined loss of IFN-? and the ?-common cytokines GM-CSF and IL-3. These immunodeficient mice develop chronic pulmonary inflammation and lung tumors at a high frequency. Examination of the relationship between these tumors and their inflammatory microenvironment revealed a dual role for the immune system in tumor development. The inflammatory cytokine IL-6 promoted optimal tumor growth, yet wild-type mice rejected transplanted tumors through the induction of adaptive immunity. These findings suggest a model whereby cytokine deficiency leads to oncogenic inflammation that combines with defective antitumor immunity to promote lung tumor formation, representing a unique system for studying the role of the immune system in lung tumor development.

SUBMITTER: Dougan M

PROVIDER: S-EPMC3104747 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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A dual role for the immune response in a mouse model of inflammation-associated lung cancer.

Dougan Michael M Li Danan D Neuberg Donna D Mihm Martin M Googe Paul P Wong Kwok-Kin KK Dranoff Glenn G

The Journal of clinical investigation 20110502 6

Lung cancer is the leading cause of cancer death worldwide. Both principal factors known to cause lung cancer, cigarette smoke and asbestos, induce pulmonary inflammation, and pulmonary inflammation has recently been implicated in several murine models of lung cancer. To further investigate the role of inflammation in the development of lung cancer, we generated mice with combined loss of IFN-γ and the β-common cytokines GM-CSF and IL-3. These immunodeficient mice develop chronic pulmonary infla ...[more]

PMID: 21537082

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Project description:BackgroundCigarette smoke exposure is the major risk factor for developing COPD. Presently, available COPD treatments focus on suppressing inflammation and providing bronchodilation. However, these options have varying efficacy in controlling symptoms and do not reverse or limit the progression of COPD. Treatments strategies using bacterial-derived products have shown promise in diseases characterized by inflammation and immune dysfunction. This study investigated for the first time whether a novel immunotherapy produced from inactivated Klebsiella (hereafter referred to as KB) containing all the major Klebsiella macromolecules, could attenuate cigarette smoke exposure-induced immune responses. We hypothesized that KB, by re-directing damaging immune responses, would attenuate cigarette smoke-induced lung inflammation and bronchoalveolar (BAL) cytokine and chemokine production.MethodsKB was administered via a subcutaneous injection prophylactically before initiating a 3-week acute nose-only cigarette smoke exposure protocol. Control mice received placebo injection and room air. Total BAL and differential cell numbers were enumerated. BAL and serum were analysed for 31 cytokines, chemokines, and growth factors. Lung tissue and blood were analysed for Ly6CHI monocytes/macrophages and neutrophils. Body weight and clinical scores were recorded throughout the experiment.ResultsWe demonstrate that KB treatment attenuated cigarette smoke-induced lung inflammation as shown by reductions in levels of BAL IFNγ, CXCL9, CXCL10, CCL5, IL-6, G-CSF, and IL-17. KB additionally attenuated the quantity of BAL lymphocytes and macrophages. In parallel to the attenuation of lung inflammation, KB induced a systemic immune activation with increases in Ly6CHI monocytes/macrophages and neutrophils.ConclusionsThis is the first demonstration that subcutaneous administration of a microbial-based immunotherapy can attenuate cigarette smoke-induced lung inflammation, and modulate BAL lymphocyte and macrophage levels, while inducing a systemic immune activation and mobilization. These data provide a foundation for future studies exploring how KB may be used to either reverse or prevent progression of established emphysema and small airways disease associated with chronic cigarette smoke exposure. The data suggest the intriguing possibility that KB, which stimulates rather than suppresses systemic immune responses, might be a novel means by which the course of COPD pathogenesis may be altered.

Dataset Information

A dual role for the immune response in a mouse model of inflammation-associated lung cancer.

Publications

A dual role for the immune response in a mouse model of inflammation-associated lung cancer.

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