Abstract 1343: Toll-like Receptor 9 (TLR9) stimulation results in a change in tumor macrophage infiltration associated with an anti tumor effect in a mouse model of lung adenocarcinoma induced by oncogenic K-ras

Abstract

Abstract Microenvironment and immune system contribute to tumor escape in cancer. Toll-like Receptor 9 (TLR9) stimulation with a CpG ODN (PF-3512676) was expected to restore antitumor response in a mouse model of lung adenocarcinoma (ADC) induced by oncogenic K-ras (K-rasLA1 mice). In these mice, TLR9 was not expressed by normal lung, nor tumor cells but only by the inflammatory tumor component as shown by TLR9 mRNA quantification by real time quantitative fluorescent PCR and immunohistochemistry. Sixteen week-old K-rasLA1 mice received PF-3512676 (n=13) or vehicle (n=13) through subcutaneous administration for 3 weeks. Mice were killed after completion of treatment. During autopsy procedure, lesions were counted on lung surfaces by investigators blinded to treatment group. Compared to the vehicle group, there was a decrease of tumor cell proliferation (PCNA staining score: 28.5% ± 1 vs 22.4% ± 0.8; p<0.0001, respectively) and an increase of tumor cell apoptosis (CC3 western blot and staining score: 0.058% ± 0.01 vs 0.105% ± 0.01; p=0.0154, respectively) in the PF group. No effect was observed on the autopsy count (26.5 ± 3.7 tumors vs 24 ± 2.3; p=0.85) nor on the histological count (27 ± 3.4 tumors vs 20.7 ± 2.2; p=0.23). Macrophage infiltration studied by F4/80 staining was different between the two groups with a higher number of macrophages inside the tumors in PF group while a higher number in peritumor area in the vehicle group (intra/peritumoral macrophage ratio: 3.35 ± 0.5, PF group vs 1.68 ± 0.1 vehicle, p=0.003). LKR-13, a lung ADC cell line derived from K-rasLA1 mice, does not express TLR9 and was resistant to treatment with PF in vitro. However, LKR-13 cells grown as syngeneic tumors recruited macrophages, and those tumors regressed in response to treatment with PF. These findings provide evidence that TLR9 stimulation might reduced the expansion of lung ADC induced by oncogenic K-ras and suggest that phenotypic modification of macrophages may contribute to ADC regression. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1343.