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Epithelial to mesenchymal transition to predict immune resistance in non-small cell lung cancer
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International audience. IntroductionLung cancer remains the main cause of death worldwide, despite significant clinical benefit by immunotherapy (IO). Programmed Death-Ligand 1 (PD-L1) used as a biomarker is insufficient to predict responses with many patients experiencing resistance to IO. The identification of biomarkers able to predict resistance to IO remains a timely challenge for oncologists. Epithelial-Mesenchymal Transition (EMT) is a well-known pathway inducing tumor aggressivity. ITK directed against AXL, a main actor of EMT, have been developed in extra-thoracic malignancies. We previously demonstrated a positive correlation between vimentin and PD-L1 expression. We hypothesize that a mesenchymal polarization is associated with immune resistance in lung cancer.MethodsWe pooled EMT signatures into 120 NSCLC cell lines (GSE32036) to enhance EMT characterisation based on transcriptomic signature. We then explored biological characteristics associated with immune response into 503 lung adenocarcinoma and 502 lung squamous cell carcinoma from the Tumor Cancer Genome AtlasResultsWe developed a signature able to identify EMT traits in NSCLC and then restricted this signature to 2 markers: AXL and VIM. AXL and VIM co-expression identified mesenchymal from epithelial tumors in both histological sub-types (p<0.0001). Enrichment pathway highlighted chemokine overexpression associated with cytokine signalling specifically in mesenchymal specimens (p<0.05). Mesenchymal tumors were enriched into actors of IL-36 signalling, associated with resistance to IO (p<0.0001, FDR 0,012). Inversely, epithelial tumors were enriched into actors of IL-10 signalling, associated with sensibility to IO (p<0,0001, FDR<0.0001). Chemokine expression has also been described as predictor of IO sensibility. We thus performed an independent clustering based on chemokine expression and identified 2 groups strongly associated with EMT (p<0.0001). Using predictive signatures of response to IO, mesenchymal tumors exhibited higher scores than epithelial tumors (p<0.0001).ConclusionEMT consideration would predict resistance to IO and could help to define a subset of patients benefiting from IO. This work will help to enhance knowledge and further define new perspective of research in onco-immunology field.
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