RT Journal Article SR Electronic T1 Evolution of immune escape mechanisms in the progression from preinvasive to invasive human lung adenocarcinoma JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.04.17.046540 DO 10.1101/2020.04.17.046540 A1 Nasser K. Altorki A1 Alain C. Borczuk A1 Vivek Mittal A1 Olivier Elemento A1 Timothy E. McGraw YR 2020 UL http://biorxiv.org/content/early/2020/04/18/2020.04.17.046540.abstract AB The tumor microenvironment (TME) of lung adenocarcinoma (LUAD) precursor lesions has not been described. We interrogated by multiplex immunofluorescence the TME of preinvasive and invasive Stage 1A LUADs selected by computer tomography (CT) scan-density. Pure non-solid (p-NS) CT density nodules are preinvasive/minimally invasive, whereas solid CT density nodules are frankly invasive cancers. Our data reveal an intensely immune-suppressive immune TME in p-NS tumors characterized by an increase in Treg cells and a decrease in cytotoxic T cells relative to normal lung. The TME of the solid tumor group, more advanced lesions than the p-NS yet still early in disease development, were increasingly more immune-suppressive. Provocatively, there was a further increase in both Treg cells and cytotoxic T cells, establishing a nascent albeit ineffective anti-tumor immune response in transition from preinvasive p-NS to invasive solid tumors. Regulatory T cells play a dominant role throughout progression, while additional immune evasive mechanisms are employed at different stages of disease progression, including T cell exclusion from cancer cell nests early and activation of immune checkpoints later. Our study establishes that different immune-targeted strategies are required to intercept disease progression at these two distinct early points of lung cancer development.Statement of Significance Using multiplexed IF, we compared the cellular composition and activation state of the tumor immune microenvironment between pre/minimally invasive and frankly invasive adenocarcinoma. We found a progressive increase in immunosuppressive mechanisms in association with disease progression suggesting that Interception strategies should be specifically tailored based on underlying immune escape mechanismsCompeting Interest StatementThe authors have declared no competing interest.TMEtumor microenvironmentLUADlung adenocarcinomap-NSPure non-solidAISadenocarcinoma in-situMIAminimally invasive adenocarcinomaGZBgranzyme BROIregion of interestCTcomputer tomographyEGFREGF receptorTMAtumor microenvironment