Tumor-intrinsic LKB1-LIF signaling axis establishes a myeloid niche to promote immune evasion and tumor growth

Abstract

SUMMARYTumor mutations can influence the surrounding microenvironment leading to suppression of anti-tumor immune responses and thereby contributing to tumor progression and failure of cancer therapies. Here we use genetically engineered lung cancer mouse models and patient samples to dissect howLKB1mutations accelerate tumor growth by reshaping the immune microenvironment. Comprehensive immune profiling ofLKB1-mutant vs wildtype tumors revealed dramatic changes in myeloid cells, specifically enrichment of Arg1+interstitial macrophages and SiglecFHineutrophils. We discovered a novel mechanism whereby autocrine LIF signaling inLkb1-mutant tumors drives tumorigenesis by reprogramming myeloid cells in the immune microenvironment. Inhibiting LIF signaling inLkb1-mutant tumors, via gene targeting or with a neutralizing antibody, resulted in a striking reduction in Arg1+interstitial macrophages and SiglecFHineutrophils, expansion of antigen specific T cells, and inhibition of tumor progression. Thus, targeting LIF signaling provides a new therapeutic approach to reverse the immunosuppressive microenvironment ofLKB1-mutant tumors.