T helper 17 cells play a critical pathogenic role in lung cancer.

ABSTRACT: Lung cancer development is associated with extensive pulmonary inflammation. In addition, the linkage between chronic obstructive pulmonary disease (COPD) and lung cancer has been demonstrated in population-based studies. IL-17-producing CD4 helper T cells (Th17 cells) play a critical role in promoting chronic tissue inflammation. Although Th17 cells are found in human COPD and lung cancer, their role is not understood. We have thus used a mouse model of lung cancer, in which an oncogenic form of K-ras (K-ras(G12D)), frequently found in human lung cancer, is restrictedly expressed in lung epithelial cells [via Clara cell secretory protein (CCSP(cre))]. In this model, Th17 and Treg but not Th1 cells were found enriched at the tumor tissues. When CCSP(cre)/K-ras(G12D) mice were weekly challenged with a lysate of nontypeable Haemophilus influenza (NTHi), which induces COPD-type inflammation and accelerates the tumor growth, they showed greatly enhanced Th17 cell infiltration in the lung tissues. Lack of IL-17, but not IL-17F, resulted in a significant reduction in lung tumor numbers in CCSP(cre)/K-ras(G12D) mice and also those treated with NTHi. Absence of IL-17 not only resulted in reduction of tumor cell proliferation and angiogenesis, but also decreased the expression of proinflammatory mediators and reduced recruitment of myeloid cells. Depletion of Gr-1(+)CD11b(+) myeloid cells in CCSP(cre)/K-ras(G12D) mice suppressed tumor growth in lung, indicating Gr-1(+)CD11b(+) myeloid cells recruited by IL-17 play a protumor role. Taken together, our data demonstrate a critical role for Th17 cell-mediated inflammation in lung tumorigenesis and suggest a novel way for prevention and treatment of this disease.

SUBMITTER: Chang SH 

PROVIDER: S-EPMC3992670 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature