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

Our plain-English summary of A dual role for the immune response in a mouse model of inflammation-associated lung cancer, by M. Dougan, D. Li, D. Neuberg, et al (The Journal of Clinical Investigation, 2011).

The study

• Authors: M. Dougan, D. Li, D. Neuberg, M. Mihm, P. Googe, K.K. Wong, G. Dranoff
• Journal: The Journal of Clinical Investigation
• Published: 2011;121(6):2436-46
• Cited by: 86 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory study in mice. No asbestos or cigarette smoke was given; the authors mentioned both only as background, as causes of lung cancer that induce lung inflammation. They bred mice lacking three immune signaling proteins (GM-CSF, IL-3 and IFN-γ), called TKO mice, onto the BALB/c strain. Examined at 12–14 months of age, 24 of 24 TKO mice had lung cancer. None of the comparison mice did: 0 of 9 normal (wild-type) mice, 0 of 15 mice lacking only GM-CSF and IL-3, and 0 of 8 mice lacking only IFN-γ. The tumors resembled adenocarcinomas and arose amid chronic lung inflammation. TKO mice given normal bone marrow did not develop lung cancer (0 of 4). Lowering the inflammatory signal IL-6 in tumor cells slowed their growth. Transplanted tumors grew more slowly in normal mice than in TKO mice or in mice lacking adaptive immunity. The authors concluded that altered immune function led both to tumor-promoting inflammation and to failure of antitumor immunity. Mice also lacking RAG-2 developed overwhelming pneumonia; most had to be euthanized before 3 months, so lung cancer incidence could not be assessed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: animal experiment (genetically modified mice, bone marrow transplantation, tumor cell lines and tumor transplantation)
• Who was studied: Laboratory mice on the BALB/c background lacking GM-CSF, IL-3 and IFN-γ (TKO), compared with wild-type, GM-CSF/IL-3 double-deficient (DKO), IFN-γ-deficient, BL6 TKO and RAG-KO mice. The lung cancer table included 9 WT, 24 TKO, 15 DKO and 8 IFN-γ-deficient mice sacrificed at 12–14 months. The work was done at Dana-Farber Cancer Institute, Boston.
• Exposure: No asbestos, cigarette smoke or other carcinogen exposure was studied. The exposure was a genetic deficiency in the immune cytokines IFN-γ, GM-CSF and IL-3. Asbestos and cigarette smoke are mentioned only as background, as lung cancer factors that induce pulmonary inflammation.
• Main results:
  • At 12–14 months, lung cancer was found in 24/24 BALB/c TKO mice, 0/9 WT, 0/15 DKO and 0/8 IFN-γ-deficient mice. The tumors required deficiency in both GM-CSF/IL-3 and IFN-γ.
  • In BALB/c TKO mice, chronic lung inflammation was present at 2–3 months of age. By 6–9 months, more than half had frank lung malignancies.
  • In bone marrow chimera experiments, lung cancer was found in 0/4 TKO mice given WT marrow and in 3/3 TKO mice given TKO marrow (per Table 2). The text describes the control group as n = 3 with 2 tumors and 1 dysplastic lesion. WT mice given TKO marrow had 0/4 lung cancer.
  • BALB/c TKO mice had higher levels of IL-6 (P = 0.002) and TNF-α (P = 0.04) in lung lavage fluid than control mice.
  • Knocking down IL-6 in a tumor cell line (KD-2) slowed growth in culture (P < 0.0001) and in TKO mice (P = 0.005). Mice carrying these tumors survived longer (P = 0.02).
  • Combined IKK1/IKK2 inhibition, which blocks NF-κB signaling, reduced the viability of the tumor cells (P = 0.001).
  • Transplanted TKO tumors grew more slowly in WT mice than in TKO mice (P < 0.0001). They grew more rapidly in RAG-KO mice, which lack adaptive immunity, than in WT controls (P < 0.0001).
• The authors' conclusion: The authors concluded that their findings establish a distinct model of lung cancer, dependent on altered immune function, that leads both to tumor-promoting inflammation and to failure of antitumor immunity.
• Limitations the authors state:
  • Mice deficient in GM-CSF, IL-3, IFN-γ and RAG-2 developed overwhelming pneumonia, and most had to be sacrificed before 3 months of age. As a result, lung cancer incidence could not be assessed in them.
  • The authors did not know whether IL-6 has a critical function in the early stages of tumor formation.
  • It remained to be established whether the Gr-1+CD11b+ myeloid cells found in the lungs were truly immune-suppressive.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Inflammation, Lung Cancer, Cytokine.

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