A dual role for the immune response in a mouse model of inflammation-associated lung cancer
Michael Dougan, … , Kwok-Kin Wong, Glenn Dranoff
Michael Dougan, … , Kwok-Kin Wong, Glenn Dranoff
Published May 2, 2011
Citation Information: J Clin Invest. 2011;121(6):2436-2446. https://doi.org/10.1172/JCI44796.
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Research Article Oncology

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-γ and the β-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.

Authors

Michael Dougan, Danan Li, Donna Neuberg, Martin Mihm, Paul Googe, Kwok-Kin Wong, Glenn Dranoff

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Figure 5

Knockdown of IL-6 reduces the proliferation of a BALB/c TKO lung tumor cell line.

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Knockdown of IL-6 reduces the proliferation of a BALB/c TKO lung tumor c...
(A) 1 × 104 MDAC8 cells infected with lentiviruses encoding nontargeting shRNA (scr), or shRNA against IL-6 (KD-1 and KD-2) were cultured for 3 days in RPMI; supernatants were harvested, and total IL-6 was measured by ELISA. (B) Western blot for cytoplasmic pERK (top panels) or nuclear (nuc) STAT3 (bottom panels) using lysates from IL-6–knockdown or control (scr) MDAC8 cells. (C and D) In vitro (C) and in vivo (D) growth of MDAC8 cells expressing IL-6 shRNA compared with cells expressing nontargeting controls. (C) 1 × 104 cells were cultured in RPMI. Growth was measured by CellTiter-Glo (CTG, Promega). (D) Left panel: 4 × 104 cells were injected subcutaneously into BALB/c TKO mice, with 8 animals per group. Right panel: Survival of mice harboring tumors. (E) Comparison of IL-6 production from ex vivo cultured IL-6 KD-2 or control MDAC8 cell lines following growth in a secondary host (ex vivo) or after in vitro culture (baseline). Three to 4 tumors were used per group. (A–E) Results are representative of at least 2 independent experiments, with 6–8 replicates per experiment. Error bars represent the SEM for the experiment shown.