Global evolution of the tumor microenvironment associated with progression from preinvasive/minimally invasive to invasive human lung adenocarcinoma

To investigate changes in the tumor microenvironment (TME) during lung cancer progression, we interrogate tumors from two computer tomography (CT) defined groups. Pure non-solid (pNS) CT density nodules contain preinvasive/minimally invasive cancers and solid density nodules invasive cancers. Profiling data reveal a dynamic interaction between the tumor and its TME throughout progression. Alterations in genes regulating the extracellular matrix and genes regulating fibroblasts are central at the preinvasive state. T cell-mediated immune suppression is initiated in preinvasive nodules and sustained with rising intensity through progression to invasive tumors. Reduced T cell infiltration of the cancer cell nests is more frequently associated with preinvasive cancers, possibly until tumor evolution leads to a durable, viable invasive phenotype accompanied by more varied and robust immune suppression. Upregulation of immune checkpoints occurs only in the invasive nodules. Throughout progression an effector immune response is present but is effectively thwarted by the immune-suppressive elements. Normal lung, pure non-solid CT scan density adenocarcinoma nodules and solid density nodules were profiles by RNAseq to reveal transcriptome differences associated with progression from normal lung to preinvasive/minimally invasive to invasive lung cancer.