Abstract
Nowadays, anti-TNF therapy remarkably improves the medical management of ulcerative colitis (UC), but approximately 40 % of patients do not respond to this treatment. In this study, we used 79 anti-TNF-naive patients with moderate-to-severe UC from four cohorts to discover alternative therapeutic targets and develop a personalized medicine approach that can diagnose UC non-responders (UCN) prior to receiving anti-TNF therapy. To this end, two microarray data series were integrated to create a discovery cohort with 35 UC samples. A comprehensive gene expression and functional analysis was performed and identified 313 significantly altered genes, among which IL6 and INHBA were highlighted as overexpressed genes in the baseline mucosal biopsies of UCN, whose cooperation may lead to a decrease in the Tregs population. Besides, screening the abundances of immune cell subpopulations showed neutrophils' accumulation increasing the inflammation. Furthermore, the correlation of KRAS signaling activation with unresponsiveness to anti-TNF mAb was observed using network analysis. Using 50x repeated 10-fold cross-validation LASSO feature selection and a stack ensemble machine learning algorithm, a five-mRNA prognostic panel including IL13RA2, HCAR3, CSF3, INHBA, and MMP1 was introduced that could predict the response of UC patients to anti-TNF antibodies with an average accuracy of 95.3 %. The predictive capacity of the introduced biomarker panel was also validated in two independent cohorts (44 UC patients). Moreover, we presented a distinct immune cell landscape and gene signature for UCN to anti-TNF drugs and further studies should be considered to make this predictive biomarker panel and therapeutic targets applicable in the clinical setting.