Lung cancers continue to rank among the deadliest malignancies worldwide despite promising newtherapeutic advances. Recently approved options for the most common type, Non-Small Cell LungCancer (NSCLC) now include the immune checkpoint inhibitors nivolumab and pembrolizumab.While these PD-1 (programmed cell death protein-1)-blocking agents have been shown to extendNSCLC patient survival, currently only a subset of patients benefit from these immunotherapies.Tumor and/ or immune cell expression of PD-ligand 1 (PD-L1) may help guide patient selection foranti-PD1 therapies, but does not fully correlate with clinical outcome. Improving ourunderstanding of biomarkers predictive of response and resistance to such immunotherapies couldimprove patient selection criteria and their clinical response rates. Alterations in oncogenicdrivers of NSCLCs can predict response to targeted therapies but whether they can also serve aspredictive biomarkers for immunotherapies remains unclear. As the immune composition of thetumor microenvironment has been shown to correlate with response to immunotherapies in othercancer indications (e.g. Tumeh et al, 2014), characterizing the immune landscape across differentNSCLC genetic subtypes could clarify whether specific alterations in EGFR, K-Ras, FGFR, or otheroncogenes may help to stratify patients likely to respond to immunotherapies, as well as suggestadditional biomarkers of response beyond PD-L1. We therefore are profiling the immune landscapeacross 50+ human NSCLC cases by flow cytometry and are integrating this analysis with clinical and histopathologic characteristics, next generation sequencing, mRNA expression, andimmunohistochemistry. We are also immuno-profiling several different established autochthonousgenetically engineered mouse models (GEMMs) of NSCLC, including those driven by EGFR-, K-Ras-,or FGFR activating mutations. These GEMMs share many features observed in the immune profilesof genetically analogous human lung adenocarcinomas, particularly at the levels of lymphocyteinfiltration and T cell exhaustion marker expression. By evaluating the immune landscapes of bothhuman and murine tumors, we are clarifying not only the associations between defined geneticalterations and immune phenotypes, but also the specific GEMMs that most closely recapitulate thecomplex microenvironmental features of genetically analogous human NSCLC cases. These effortsare facilitating the further advancement of NSCLC GEMMs for improved pre-clinical evaluations ofimmunotherapies, and the rationale for new combination therapies.