Background: The complement system can exert pro- or anti-tumorigenic functions based on different tumour types and contexts, suggesting novel perspectives for therapeutic targeting in selected subgroups of patients [1]. We aimed at developing an innovative prognostic tool based on the in situ quantification of several complement components for the prediction of malignant pleural mesothelioma (MPM) patient outcome, introducing the definition of “Complement Score”.
Methods: Bioinformatics analysis via GEPIA and UALCAN (TCGA-MESO); immunohistochemistry on MPM tissue microarrays (TMAs, n = 88) and whole tissue sections (n =17); clinical information collection and statistics analysis.
Results: Bioinformatics analysis of genes encoding for complement activation components (n = 27) and regulators/receptors (n = 29) allowed the selection of four promising markers in MPM: the mRNA expression of C1S, SERPING1, CFB and CFI resulted to be positively correlated with patient overall survival. C1q was included in further analysis due to its abundance in MPM microenvironment [2]. Protein expression of the selected complement components was evaluated both on TMAs and whole tissue sections of MPM patients, being expressed as percentage of tumour cell positivity, immune cell positivity and deposit. C1s, C1INH, CFB and CFI displayed cytoplasmic positivity of tumour cells, but also of immune cells and deposit, whereas C1q presence was only detected as deposit or positivity of monocytes/macrophages. Univariate analyses were performed in order to correlate the expression of each complement component with MPM histotype, TILs (CD4+, CD8+, CD19+), tumor proliferative activity (Ki-67), PD-L1 expression, overall survival. Survival analysis showed that C1qHIGH (Log-rank test, χ2 = 6.01; p = 0.01) and C1INHHIGH (Log-rank test, χ2 = 5.13; p = 0.02) patients displayed significantly increased survival.
Conclusions: Complement Score could be hopefully used in the future as a tool to stratify MPM patients, directing each patient to a personalized treatment, and its application could be potentially extended to other solid tumours, unveiling the “double-edged sword” role of complement system in cancer.
