Th126 - Phenotyping of Human UC Colonic Tissue Reveals Inflammatory Pathway Gene Expression in PD-1+ Conventional and Regulatory T Cells Which Overlap with Those Regulated by Rosnilimab in a Mouse Model of Colitis

Abstract Text: In ulcerative colitis (UC), the lamina propria has multiple T cell subtypes that express the co-inhibitory receptor, PD-1, including conventional T effector memory cells and T peripheral helper cells (Tph). The reduction of PD-1+ Tph cells is correlated with remission, therefore PD-1 receptor agonists, such as rosnilimab, are a promising class of therapeutics that leverage immune homeostatic mechanisms to regulate T cell activity for treatment of inflammatory diseases, including UC.
PD-1+ T cell subsets were characterized via secondary analyses of a single-cell data set from UC patient-derived colonic tissue and showed PD-1+ CD4 conventional T cells and PD-1+ Tregs had increased JAK-STAT, TNF, and NF-κB estimated pathway activity compared to PD-1– cells. PD-1+ Tregs had increased expression of genes associated with a pro-inflammatory phenotype, including TNF, TBX21(TBET), and IL12RB2, consistent with the hypothesis that PD-1+ Tregs may be a pro-inflammatory subtype. In a preclinical study, genes in pathways involved in human UC (“Signaling by interleukins” (e.g., Il6) and “Chemokine receptors bind chemokines” (e.g., Ccl20)) were upregulated in mouse colitis, compared to naïve animals. These genes, in addition to the barrier gene Muc3 and fibrosis-associated Mmp9, were normal in rosnilimab-treated mice while dysregulated in colitis, and corresponds to published data showing rosnilimab reduced body weight loss, reduced inflammation of the colon, and reduced infiltration of CD4 T cells in mouse colitis. These analyses suggest that PD-1 is upstream of multiple clinically validated drivers of UC, supporting the scientific rationale for studying rosnilimab in an ongoing Phase 2 study in UC (NCT06127043).