Abstract B53: Intra-tracheal delivery of low-dose bacterial lipopolysaccharides protects against tumor formation in the KP lung adenocarcinoma model

Abstract

Abstract While genetically engineered mouse models (GEMM) of lung adenocarcinoma (LUAD) recapitulate some aspects of the histopathology of human LUAD, they poorly reflect the inflammatory components of human LUAD. In this study, we performed repeated weekly intra-tracheal dosing with bacterial lipopolysaccharides (LPS) after adenoviral-Cre (AdCre) delivery into K-RasLSL-G12D/+; p53fl/fl mice to examine the effect of inflammation on lung adenocarcinoma progression. LPS has been historically used to study the acute inflammatory response both locally and systemically in animal models. The typical response involves recruitment and activation of innate immune cells, mainly neutrophils and macrophages, to the site of delivery and/or production of pro-inflammatory cytokines including TNF-alpha, IL-6 and IL-1. Repeated long-term conditioning with low-dose LPS results in alveolar wall thickening as observed by uCT and the accumulation of lymphoid aggregates in the lung. However, surprisingly, LPS conditioning drastically reduced tumor incidence from 75% in the control group to 25%. Furthermore, starting LPS delivery four weeks after AdCre instillation, to eliminate any possible LPS effects on adenoviral delivery and K-Ras induction/p53 loss, still resulted in drastically reduced lung tumor formation suggesting that the effect results from an LPS-induced immune response. Two LPS instillations were sufficient to elicit this effect. Short-term antibody-mediated depletion of neutrophils or CD8+ T cells also did not abrogate the effect of LPS on tumor formation. In vitro re-stimulation of CD8+T cells (from blood or spleen) from tumor-free animals with KP tumor cells did not elicit interferon-gamma production, as assayed by intra-cellular cytokine staining and ELISPOT, suggesting that a cell type other than CD8+ T-cells or neutrophils mediates the effect. Interestingly and consistent with the inhibitory effect of LPS on tumor formation, multiple pneumonia diagnoses in COPD patients/smokers has been associated with a lower odds ratio of developing lung cancer in humans. Identifying the cell-type (s) and mechanisms mediating the anti-tumor effect of LPS will help in defining the aspects of immune response that inhibit LUAD progression. Citation Format: Ganapathy Sriram, Lauren Milling, Darrell J. Irvine, Michael B. Yaffe. Intra-tracheal delivery of low-dose bacterial lipopolysaccharides protects against tumor formation in the KP lung adenocarcinoma model [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B53.