C1-inhibitor is a novel prognostic factor in malignant pleural mesothelioma and in serous ovarian carcinoma

Background: Complement components display controversial roles in different tumour types and contexts, with ambivalent prognostic impact1. They can be secreted by tumor, stromal, and tumor-infiltrating immune cells in the tumor microenvironment (TME), or derive from circulation. Here, we aimed to determine the prognostic significance of C1-inhibitor (C1-INH) in malignant pleural mesothelioma (MPM) and serous ovarian cancer (OVCA) and characterize its expression in the TME. Methods: Bioinformatics analysis (TCGA-MESO and TCGA-OV); immunohistochemistry (IHC); Digital Spatial Profiling (DSP); primary cell isolation; Real-Time qPCR; Western blot; ELISA. Results: Bioinformatics analyses unveiled that increased SERPING1 mRNA expression is a favorable prognostic factor in both MPM (particularly in epithelioid histotype) and OVCA, being associated with prolonged overall survival of the patients. IHC analysis revealed a high expression of C1-INH in tumour cells and, to a lesser extent, in immune cells. We confirmed that C1-INHHIGH MPM (n=17; χ2=5.13; p=0.02) and C1-INHHIGH OVCA (n=14;χ2=4.85; p=0.02) patients displayed significantly increased overall survival. Real-Time qPCR of isolated primary cells confirmed that MPM and OVCA tumour cells can produce C1-INH at high levels. Deconvolution analysis suggested that cancer-associated fibroblasts (CAFs), macrophages, and endothelial cells are also among the leading producers of C1-INH in the TME. C1-INH protein quantification via ELISA in tumour cell supernatants and pleural/peritoneal fluids highlighted high levels of C1-INH, particularly in ovarian cancer, and a strong correlation with enzymatic functionality. Interestingly, DSP of biphasic MPM cases revealed that C1-INH is involved in epithelial-to-sarcomatoid transition, probably due to a different grade of tumour cellularity. Conclusions: C1INH is a favorable prognostic factor in MPM and OVCA. Further studies will be needed to unveil its potential role in modulating the TME and tumour progression, paving the way to the promising development of novel C1-INH-based therapeutic strategies in these cancers.