T helper 17 cells play a critical pathogenic role in lung cancer.
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.
Departments of Immunology and Pulmonary Medicine, Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX 77054.
Seon Hee
SH
Chang
Seyedeh Golsar
SG
Mirabolfathinejad
Harshadadevi
H
Katta
Amber M
AM
Cumpian
Lei
L
Gong
Mauricio S
MS
Caetano
Seyed Javad
SJ
Moghaddam
Chen
C
Dong
D000818:Animals; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D011905:Genes, ras / Q000235:genetics; D006193:Haemophilus influenzae / Q000276:immunology; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000150:complications / Q000276:immunology* / Q000503:physiopathology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D011014:Pneumonia / Q000150:complications / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D058504:Th17 Cells / Q000276:immunology*; D014598:Uteroglobin / Q000378:metabolism
D017931:DNA Primers; C556390:Scgb1a1 protein, mouse; D014598:Uteroglobin
interleukin 17; lung adenocarcinoma