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Background LKB1 mutant lung adenocarcinoma is a frequently occurring and aggressive genetic subtype of lung cancer associated with poor prognosis and diminished response rates to immune checkpoint blockade. However, the mechanism in which this mutation regulates the tumor immune microenvironment and immunotherapy responses remains unknown. Identifying the pathway which LKB1 mutant lung tumors utilize to alter the immune microenvironment can lead to the development of novel immune based therapies.Methods We generated autochthonous LKB1 mutant tumors utilizing a Kras-driven lung adenocarcinoma genetically engineered mouse model combined with in vivo CRISPR/Cas9 editing. A lentivirus expressing a sgRNA targeting LKB1 and Cre recombinase was intratracheally administered to KrasLSL- G12D/+ Tp53 fl/fl Rosa26LSL-Cas9-P2A-GFP mice to initiate lung tumors with deletion of LKB1. Eleven weeks after tumor initiation, immune cells and tumor cells were isolated from the lungs and comprehensive immune profiling was performed using modalities including flow cytometry, immunofluorescence, and the single cell platform ExCITE-seq.Results Single-cell analysis revealed that LKB1 mutant lung tumors promote the infiltration of SiglecFHi neutrophils and Arg1+ interstitial macrophages which have transcriptional programs associated with immune evasion. Consistent with this immunosuppressive microenvironment, we observed reduced production of TNFα and IFNγ by CD4 and CD8 T cells isolated from LKB1 mutant lung tumors. Through gene expression analysis of tumor cells, we discovered LKB1 mutant tumors upregulate the cytokine Leukemia Inhibitory Factor (LIF). Genetic deletion of LIFR, the receptor for LIF, specifically on LKB1 mutant tumors reversed the immunosuppressive myeloid cell infiltrate and lead to expansion of antigen specific T cell clones as revealed by our ExCITE-seq analysis. These findings demonstrate that LKB1 mutant lung tumors harness an autocrine LIF signaling loop to remodel the tumor microenvironment. Single-cell analysis of LKB1 mutant tumor cells revealed that LIF induces tumor plasticity and the emergence of an inflammatory tumor cell state expressing the transcription factor Sox17. Finally, administration of a LIF neutralizing antibody eliminated the Sox17 + tumor cell state resulting in a significant reduction of SiglecF Hi neutrophils and Arg1 + interstitial macrophages corresponding with an increase in anti-tumor T cell responses ultimately leading to impaired tumor proliferation.Conclusions LKB1 mutant tumors engage in autocrine LIF signaling to induce a Sox17 dependent inflammatory program to remodel the immune microenvironment with immunosuppressive myeloid cells to promote tumorigenesis (figure 1). Therefore, blocking LIF signaling may be an effective novel therapeutic strategy to target tumor cell states driving immune evasion and treatment resistance in solid tumors with high expression of LIF.Ethics Approval This studied contains animal research that has been approved by IACUC (IA16-01627).Abstract 1263 Figure 1Autocrine LIF Signaling in LKB1 mutant lung cancer LKB1 mutant lung tumors utilize autocrine LIF signaling to promote the recruitment of immunosuppressive macrophages and neutrophils to dampen anti-tumor T cell responses