LSC Abstract – Host-environmental IL-1b drives mutant KRAS-IKKa addiction in malignant pleural effusion

Introduction Malignant pleural effusion (MPE) is primarily an immune-mediated manifestation of pleural-metastasized cancers, particularly adenocarcinomas that harbour KRAS mutations. We have previously determined that NF-κB activation in pleural tumor cells drives MPE formation, but the NF-kB pathways involved are obscure. Aims and objectives To investigate the relationship between mutant KRAS presence and NF-kB activation in pleural tumor cells that leads to MPE development. Methods We profiled baseline and host-microenvironment-induced NF-κB activity of tumor cells, and examined its relationship with KRAS status. We further silenced NF-kB activating kinases in tumor cells aiming to eliminate NF-kB activity and thus MPE competence. Results We found that mutant KRAS tumor cells were MPE competent and displayed IL-1b-induced IKKa nuclear translocation that was lost when KRAS was silenced. In contrast, wt KRAS cells did not form MPE and did not respond to IL-1b with nuclear IKKa shuttling. IKKa, but not IKKb, silencing of mutant KRAS tumors hampered their ability for MPE formation, suggesting a mutant KRAS -IKKa addiction in the pleural tumor cell during MPE development. Furthermore, IL-1b, but not TNFa, originated from host immune cells was required to sustain the MPE-competent phenotype of IKKa-addicted KRAS -mutant tumor cells. Microarray data showed that these cells secrete CXCL5 and CCl2 in response to IL-1b. Conclusions We demonstrate that KRAS -mutant tumor cells require host IL-1b signaling for MPE precipitation. This phenotype is mediated by IKKa. Acknowledgements These studies were supported by a European Research Council Starting Independent Investigator Grant (#260524). This abstract has been presented previously at the European Respiratory Society9s Lung Science Conference in March 2016 .