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Background The variability and unpredictability of drug efficacy in ulcerative colitis (UC) patients, including tofacitinib, an oral JAK1 and JAK3 inhibitor, remains a perplexing reality. The aim of this study is to identify the relevant cellular subsets and genes involved in response and/or resistance to tofacitinib using single-cell RNA sequencing (scRNA-seq). Methods Colon biopsies from UC patients starting tofacitinib treatment (10 mg twice daily) were collected from the involved region at baseline (n=9), week 8 (n=7) and week 16 (n=5). Endoscopic response was evaluated at week 16 and patients were classified as responders or non-responders based on whether they had a decrease in the endoscopic Mayo score of at least 1 point from baseline. Biopsies were immediately disaggregated and single-cell suspensions were processed using 10x Genomics Next-GEM Single Cell kit assays (Chromium 3’ v3.0). After QC filtering, a total of 61,646 cells were obtained. Additional biopsies were collected at all timepoints for validating scRNA-seq results by bulk RNA analysis (qPCR). Results Four out of nine patients enrolled in this study responded to tofacitinib treatment. Analysis of the proportions of mucosal cells identified by scRNAseq revealed a partial recovery of the epithelial and stromal cell compartments and a decrease in the total number of plasma and myeloid cells in responding patients at week 8, which was sustained at week 16 (Table 1). scRNA-seq analysis revealed a significant downregulation of SOCS1 in the CD4 and B cell populations, and of both SOCS3 and IRF1 in the neutrophil and B cell populations in all patients receiving tofacitinib treatment irrespective of endoscopic response. These results were validated by qPCR of bulk biopsy RNA (p=0.0245, p=0.0299 and p=0.0230 respectively). In contrast, S100A8 and CHI3L1 were significantly downregulated only in responders, correlating with a decrease in the proportion of mucosal inflammatory cells including neutrophils, monocytes, and inflammatory fibroblasts. Regarding prediction of outcome, a scRNA-seq comparative analysis showed that high levels of IL17A-expressing T cells at baseline significatively correlated with failure to achieve response upon tofacitinib treatment. This result was validated by qPCR of bulk biopsy RNA (p=0.0059). Conclusion Our study demonstrates the potential of using scRNAseq of intestinal biopsies not only to characterize the mechanism of action of tofacitinib, but also to describe the cellular events associated with response to this therapeutic intervention. Moreover, we show the potential of scRNAseq to identify predictors of response to tofacitinib in patients with UC.

P091 A single-cell RNAseq approach to understand and predict the efficacy of tofacitinib in Ulcerative Colitis