Project description:Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB) and introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+ PD-1+ CD8 T cells, restoring therapeutic response to PD-1 ICB for KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC patients with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.
Project description:Inactivating mutations in LKB1/STK11 are present in ~20% of non-small cell lung cancers (NSCLC) and portend poor response to anti-PD-1 immunotherapy in patients and genetically engineered mouse model (GEMMs). Here, we sought to uncover the basis for immunotherapy resistance of these tumors and to define strategies that overcome this barrier. Whereas high tumor mutational burden (TMB) often correlates with response to anti-PD1 treatment, we found that LKB1-deficient NSCLCs from non-smokers and GEMMs exhibited striking elevations in nonsynonymous mutations compared to LKB1 wildtype tumors. Correspondingly, LKB1 mutant NSCLC cell lines showed defects in both replication dependent and independent double-strand DNA break (DSB) repair, which were reversed upon LKB1 re-expression.
Project description:Inactivating mutations in LKB1/STK11 are present in ~20% of non-small cell lung cancers (NSCLC) and portend poor response to anti-PD-1 immunotherapy in patients and genetically engineered mouse model (GEMMs). Here, we sought to uncover the basis for immunotherapy resistance of these tumors and to define strategies that overcome this barrier. Whereas high tumor mutational burden (TMB) often correlates with response to anti-PD1 treatment, we found that LKB1-deficient NSCLCs from non-smokers and GEMMs exhibited striking elevations in nonsynonymous mutations compared to LKB1 wildtype tumors. Correspondingly, LKB1 mutant NSCLC cell lines showed defects in both replication dependent and independent double-strand DNA break (DSB) repair, which were reversed upon LKB1 re-expression.
Project description:STK11 (LKB1) missense somatic mutant isoforms promote tumor growth, motility and inflammation. Elucidating the contribution of somatic mutations to cancer is essential for personalized medicine. STK11 (LKB1) tumor suppressor appears to be inactivated in human cancer, however, somatic missense mutations also occur. Despite of our increased knowledge about LKB1 function, the role/s of these alterations in cancer are mostly unknown. Here, we investigated the contribution of four missense LKB1 somatic mutations in tumor biology. Three, out of the four mutants, lost their tumor suppressor capabilities and showed a deficient kinase activity. The remaining mutant conserved the enzymatic activity, but conferred an increased cell motility. Mechanistically, LKB1 mutants promoted the differential gene expression regulation of vesicle trafficking regulating molecules, adhesion molecules and cytokines, that correlated with the identified protein networks associated to the comparative secretome analysis. Notably, three mutant isoforms promoted tumor growth, and one of them induced inflammation and hemorrhagic tumors that correlated with the deregulated levels of cytokines. Altogether, our findings uncover oncogenic roles of LKB1 somatic mutations helping to understand their contribution to cancer.
Project description:LKB1 deficiency in Treg cells impairs their survival, metabolism and suppressive function. To exclude the impact of excessive inflammation on LKB1-deficient Treg cells, we generated mixed bone marrow (BM) chimeras using Foxp3-Cre WT and Foxp3-Cre Stk11 fl/fl BM cells, together with CD45.1+ BM cells. We used microarray to compare the global transcription profile of dornor-derived LKB1-deficient Tregs with WT counterparts.