Proteogenomic characterization of molecular and cellular targets for treatment-resistant subtypes in locally advanced cervical cancers.

We report proteogenomic analysis of locally advanced cervical cancer (LACC). Exome-seq data revealed predominant alterations of keratinization-TP53 regulation and O-glycosylation-TP53 regulation axes in squamous and adeno-LACC, respectively, compared to in early-stage cervical cancer. Integrated clustering of mRNA, protein, and phosphorylation data identified six subtypes (Sub1-6) of LACC among which Sub3, 5, and 6 showed the treatment-resistant nature with poor local recurrence-free survival. Elevated immune and extracellular matrix (ECM) activation mediated by activated stroma (PDGFD and CXCL1 fibroblasts) characterized the immune-hot Sub3 enriched with MUC5AC epithelial cells (ECs). Increased epithelial-mesenchymal-transition (EMT) and ECM remodeling characterized the immune-cold squamous Sub5 enriched with PGK1 and CXCL10 ECs. We further demonstrated that CIC mutations could trigger EMT activation by upregulating ETV4, and the elevation of the immune checkpoint PVR and neutrophil-like myeloid-derived suppressive cells (FCN1 and FCGR3B macrophages) could cause suppression of T-cell activation in Sub5. Increased O-linked glycosylation of mucin characterized adeno-LACC Sub6 enriched with MUC5AC ECs. These results provide a battery of somatic mutations, cellular pathways, and cellular players that can be used to predict treatment-resistant LACC subtypes and can serve as potential therapeutic targets for these LACC subtypes.