1. IL17A Regulates Tumor Latency and Metastasis in Lung Adeno and Squamous SQ.2b and AD.1 Cancer
- Author
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Chad J. Creighton, Jian Liu, Bryan M. Burt, Sung-Nam Cho, Hui Ying Tung, David B. Corry, Myunghoo Kim, Andrea Hill-McAlester, Gretchen E. Diehl, Silke Paust, Loraine Cornwell, Li-Zhen Song, Farrah Kheradmand, Sarah Perusich, Roberto F. Casal, Francesco J. DeMayo, Donald R. Lazarus, Ran You, Wen Lu, Daniel G. Rosen, and Xiaoyi Yuan
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Adoptive cell transfer ,Lung Neoplasms ,Immunology ,chemical and pharmacologic phenomena ,Adenocarcinoma ,Article ,Immunophenotyping ,Metastasis ,Malignant transformation ,Mice ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,medicine ,Carcinoma ,Animals ,Humans ,PTEN ,Neoplasm Metastasis ,Lung cancer ,Neoplasm Staging ,Smad4 Protein ,Mice, Knockout ,biology ,business.industry ,Macrophages ,Cell Cycle ,Interleukin-17 ,PTEN Phosphohydrolase ,Cancer ,hemic and immune systems ,Genomics ,medicine.disease ,Immunohistochemistry ,respiratory tract diseases ,Disease Models, Animal ,030104 developmental biology ,Carcinoma, Squamous Cell ,Disease Progression ,biology.protein ,Cancer research ,Th17 Cells ,Female ,business ,Biomarkers - Abstract
Somatic mutations can promote malignant transformation of airway epithelial cells and induce inflammatory responses directed against resultant tumors. Tumor-infiltrating T lymphocytes (TIL) in early-stage non–small cell lung cancer (NSCLC) secrete distinct proinflammatory cytokines, but the contribution of these TILs to tumor development and metastasis remains unknown. We show here that TILs in early-stage NSCLC are biased toward IL17A expression (Th17) when compared with adjacent tumor-free tissue, whereas Th17 cells are decreased in tumor infiltrating locoregional lymph nodes in advanced NSCLC. Mice in which Pten and Smad4 (Pts4d/d) are deleted from airway epithelial cells develop spontaneous tumors, that share genetic signatures with squamous- (SQ.2b), and adeno- (AD.1) subtypes of human NSCLC. Pts4d/d mice globally lacking in IL17a (Pts4d/dIl17a–/–) showed decreased tumor latency and increased metastasis. Th17 cells were required for recruitment of CD103+ dendritic cells, and adoptive transfer of IL17a-sufficient CD4+ T cells reversed early tumor development and metastasis in Pts4d/dIl17a–/– mice. Together, these findings support a key role for Th17 cells in TILs associated with the Pts4d/d model of NSCLC and suggest therapeutic and biomarker strategies for human SQ2b and AD1 lung cancer. Cancer Immunol Res; 6(6); 645–57. ©2018 AACR.
- Published
- 2018