Tocilizumab Mitigates Immune Checkpoint Inhibitor-Induced Colitis and Inhibits Tumor Growth by Targeting the IL-6-JAK2-STAT3 Signaling Pathway.

Abstract

Intestinal adverse effects induced by immune checkpoint inhibitors (ICIs) during oncology treatment reduce patients' quality of life and limit the clinical application of ICIs. To elucidate the pathogenesis of ICI-associated colitis and explore potential therapeutic strategies, we established a mouse model of PD-1 inhibitor-induced colitis. Utilizing a comprehensive suite of experimental techniques, including RNA sequencing, single-cell RNA sequencing data analysis, hematoxylin-eosin (HE) staining, immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), Western blot (WB), small-animal in vivo imaging, and tumor cell function assays, we demonstrated that IL-6 is highly upregulated in the colitis mouse model. Moreover, the IL-6-JAK2-STAT3 signaling pathway was significantly enriched, and the expression of proteins involved in this pathway was reduced following the addition of tocilizumab. This led to a decrease in colonic inflammation and a slowing of tumor growth. Therefore, we conclude that tocilizumab may attenuate PD-1 inhibitor-associated colonic inflammation and coinhibit tumor growth by targeting the IL-6-JAK2-STAT3 pathway, providing new insights for clinical treatment.