Abstract 4067: Toll-like receptor 2 deficiency enhances KRAS-driven lung cancer

Chronic infection and inflammation have been suggested to have a strong association with lung cancer in clinical and epidemiologic studies. Toll-like receptor 2 (TLR2) mediates inflammatory response and is essential in regulating innate and adaptive immunity. TLR2 has also been reported to play either pro-tumorigenesis or tumor-suppressive role depending on the oncogenic driver mutations and cell types. However, the role of TLR2 in lung cancer, especially in the lung adenocarcinoma harboring KRAS mutations, remains unknown. In an analysis using human lung adenocarcinoma cohort (TCGA RNAseq dataset), our results revealed that KRAS-mutant lung tumors showed lower TLR2 mRNA expression than the paired adjacent normal lung tissue. Furthermore, lung adenocarcinoma patients with lower TLR2 expression displayed worse survival outcome. To functionally test the role of TLR2 during KRAS-driven lung tumorigenesis, we generated a mouse model of lung adenocarcinoma mutated for K-ras, with and without TLR2 inactivation (K-ras G12D/+ TLR2 -/- and K-ras G12D/+ TLR2 +/+ , respectively). Interestingly, the tumor number and tumor area significantly increased in K-ras G12D/+ TLR2 -/- mice compared to K-ras G12D/+ TLR2 +/+ mice. In addition, the inflammatory cells in bronchoalveolar lavage (BAL), especially the alveolar monocytes, significantly increased in K-ras G12D/+ TLR2 -/- mice. Microdissected lung tumors from K-ras G12D/+ TLR2 -/- mice showed significantly higher inflammatory chemokines and cytokines gene expression (Ccl1, Ccl2, Cxcl1, Cxcl2, Cxcl5, Csf1, IL-6, Tnf) than those from K-ras G12D/+ TLR2 +/+ mice. Additionally, Cxcl1 was significantly higher in K-ras G12D/+ TLR2 -/- when BAL fluid was analyzed for cytokines/chemokines by Luminex assays. Our results suggest that TLR2 deficiency may promote KRAS-mutation driven lung tumorigenesis through increased cancer-related inflammation. Furthermore, the expression may serve as a prognostic biomarker for which the lower TLR2 expression is associated with worse survival outcome in lung adenocarcinoma patients with KRAS mutation. Citation Format: Chia-Hsin Liu. Toll-like receptor 2 deficiency enhances KRAS-driven lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4067.