Project description:Dysbiosis, or changes within the microbiome, is a common feature of solid tumors, however whether this dysbiosis directly contributes to tumor development is largely unknown. We previously characterized the human lung cancer microbiome and identified the Gram-negative Acidovorax temperans as enriched in tumors and associated with smoking status and TP53 mutations. To determine if A. temperans exposure could contribute to the development of lung cancer, we investigated its effect in a genetically engineered mouse model of lung adenocarcinoma driven by mutant Kras and Tp53. In comparison to control mice and those instilled with a commensal species Lactobacillus gasseri, we found that repeated A. temperans exposure accelerates tumor development and burden through infiltration of proinflammatory cells in the lungs. Comparing immune cell infiltrates at two timepoints revealed increased proinflammatory cells immediately following A. temperans instillation while later the number of T cells, especially IL-17+ cells, was increased. These data indicate a clear role for microbiota-induced inflammation as a key mechanism in the development of lung cancer, demonstrating that dysbiosis contributes to tumor growth.
Project description:Dysbiosis, or changes within the microbiome, is a common feature of solid tumors, however whether this dysbiosis directly contributes to tumor development is largely unknown. We previously characterized the lung cancer microbiome and identified the Gram-negative Acidovorax temperans as enriched in tumors and associated with smoking status and TP53 mutations. To determine if A. temperans exposure could contribute to the development of lung cancer, we investigated its effect in an animal model of lung adenocarcinoma driven by mutant Kras and Tp53 alleles. This revealed A. temperans exposure accelerates tumor development and burden through infiltration of proinflammatory cells in the lungs. Neutrophils exposed to A. temperans displayed a mature, pro-tumorigenic phenotype with increased cytokine signaling, with a global shift away from IL-1β signaling. Neutrophil to monocyte and macrophage signaling promoted maturation of the latter cell types which upregulated MHC II to activate CD4+ T cells. Activated T cells were then polarized to an IL-17A+ phenotype detectable in CD4+ and γδ populations. Furthermore, T17 cells shared a common gene expression profile predictive of poor survival in human LUAD cases. These data indicate a clear role for microbiota-induced inflammation as a key mechanism in the development of lung cancer, demonstrating that dysbiosis contributes to tumor growth.
