IL-11/IL-11R signal inhibition by 9MW3811 remodels immune tumor microenvironment and enhances anti-tumor efficacy of PD-1 blockade
Chang Zhang, Shasha Jiao, Dadi Zeng, Wen G. Jiang, Rongjuan Wang, Bin Zheng, Min Wang, Shuang Wang, Xun Gui
Abstract
Recent studies have uncovered evidences for pro-tumorigenic activities attributed to IL-11, prompting a renewed focus on therapeutic strategies targeting IL-11 signaling for anti-tumor treatment. Here, we introduce 9MW3811, a monoclonal antibody designed to neutralize IL-11 effectively. By disrupting the IL-11/IL-11Rα/gp130 complex, 9MW3811 inhibits JAK/STAT3 signaling, significantly reducing tumor growth in diverse mouse models. More importantly, 9MW3811 synergizes with anti-PD-1 therapy, even in PD-1 non-responsive models like CT26. Single-cell RNA-seq analysis reveals that 9MW3811 remodels the tumor microenvironment by enhancing CD8+ T cell infiltration and reversing T cell exhaustion via upregulated XCL1 and downregulated CCL7, boosting anti-tumor cytotoxicity. Furthermore, 9MW3811 counteracts PD-1-induced T cell exhaustion, with anti-PD-1 antibodies effectively mitigating PD-1 upregulation post-9MW3811 treatment. These compelling findings support ongoing clinical trials of 9MW3811, aiming to translate these preclinical insights into therapeutic benefits for cancer patients.