Investigation of γδ T cell function in a novel inducible model of lung adenocarcinoma

Abstract

Abstract γδ T cells have been demonstrated to both promote tumor growth/metastasis and to efficiently kill tumor cells. This dual role of γδ T cells has been attributed to their ability to produce either IL-17 (γδT17) or IFNγ (γδT1), the former being associated with tumor progression and the latter being associated with anti-tumor activity. γδ T cell function is influenced by multiple factors, including the recognition of stress-induced ligands, as well as cytokines and chemokines. However, the specific signals that lead to the selective activation and function of γδT17 or γδT1 subsets in different cancers remains unclear. Here, we explored these questions using a novel inducible mouse model of Kras-driven lung adenocarcinoma with or without a co-mutation in Stk11, a master regulator of metabolic pathways. Preliminary characterization of this model revealed that Kras G12D/Stk11 fl/flmice exhibited significantly greater morbidity than Kras G12Dmice. While lung leukocyte numbers did not differ significantly between Kras G12Dand Kras G12D/Stk11 fl/flmice, we noted a significantly increased frequency of γδT17, but not γδT1, subsets in Kras G12D/Stk11 fl/fllungs. Interestingly, the increased frequency of γδT17 was due to increased Vγ1 and Vγ6, but not Vγ4, γδT17 suggesting a selective expansion of these subsets. To examine a potential role for butyrophilins in these models, we assessed lung butyrophilin gene expression using qPCR. This analysis revealed increased expression of Btnl1, Btnl2, and Btnl9 in Kras G12Dlungs mice as compared to controls. Together, these results suggest that this model has the potential to shed new light on how the interaction of the tumor microenvironment with specific γδ T cell subsets affects disease pathogenesis.