P0177 The IL-6-JAK-STAT3 axis drives Immune Checkpoint Inhibitor-Related Colitis by promoting Tc17 differentiation of CD8+ T cells

Abstract Background Immune checkpoint inhibitors (ICIs) enhance anti-tumor immune responses by reversing the immunosuppressive state, but they may also disrupt immune homeostasis and induce immune checkpoint inhibitor-related colitis (IRC). Currently, its pathogenesis has not been fully elucidated. Methods we investigated the underlying pathogenesis by collecting peripheral blood samples from patients with IRC and establishing an IRC mouse model induced by the combination of dextran sulfate sodium and ICIs. Results Clinical observations have shown that the levels of pro-inflammatory cytokines such as IL-6, IL-17A and IL-21 in the peripheral blood of patients with IRC are significantly elevated, accompanied by an increase in the proportion of CD8+ T cells. By using a murine colitis model, we demonstrated that CD8+ T cells were significantly aggregated in the intestines, and the IL-6–JAK1–STAT3 signaling pathway was activated. Activation of this pathway facilitates the differentiation of CD8+ T cells into pro-inflammatory Type 17 Cytotoxic T Cells (Tc17) subsets and concurrently inhibits the development of CD8+ regulatory T cells (CD8+ Treg), thus propelling the progression of colitis. In the intervention experiments, both IL-6 inhibitor (tocilizumab) and JAK1 inhibitor (upadacitinib) were able to effectively inhibit the differentiation of Tc17 cells, promote the generation of CD8+ Treg cells, thereby improving the symptoms of colitis. Preliminary clinical exploration further suggests that upadacitinib has a good therapeutic effect on patients with refractory IRC. Conclusion Taken together, the differentiation of CD8+ T cells into the Tc17 cells, which is mediated by the IL-6–JAK1–STAT3 signaling pathway, represents a crucial mechanism underlying the onset and progression of IRC. Targeting this signaling pathway offers a novel therapeutic strategy for the clinical management of severe or refractory IRC. Conflict of interest: Dr. Xu, Shuo: No conflict of interest Zhu, Hanlong: No conflict of interest Zhou, Qiankun: No conflict of interest Sun, Changqing: No conflict of interest Wei, Juan: There is no Conflict of Interest. Wang, Fangyu: There is no Conflict of Interest.