Abstract 656: Enhanced therapeutic effect of combining denosumab with PD-1 inhibitor in advanced KRAS-mutated lung adenocarcinoma

Abstract Background: Previous studies have suggested that the combination of RANKL inhibitors and immune checkpoint inhibitors (ICIs) may potentiate the therapeutic response in lung adenocarcinoma, particularly in cases with KRAS mutations. The exact mechanisms and clinical validation of this combination therapy are yet to be fully understood. Methods: We conducted a comprehensive analysis by integrating public datasets and retrospective clinical data to examine the relationship between RANKL alterations and the tumor immune microenvironment in KRAS-mutated lung adenocarcinoma. We also investigated the signaling pathways affected by RANKL manipulation in cancer cell lines and assessed the impact on macrophage function. A prospective clinical trial was carried out to evaluate the potential of the RANKL inhibitor combined with PD-1 inhibitor therapy. Results: Our analysis revealed that the combination therapy of RANKL inhibitor with PD-1 inhibitor demonstrated improved outcomes in patients with KRAS-mutated lung adenocarcinoma. Transcriptomic data and immunohistochemical staining showed that RANKL was upregulated in these tumors, which was inversely associated with PD-L1 expression and the secretion of CXCL9, CXCL10, and CXCL11, leading to a decrease in CD8+ T cell infiltration and a more immunosuppressive environment. We found that RANKL modulated PD-L1 levels via the PI3K/AKT pathway and reduced CD8+ T cell infiltration by decreasing the expression of CXCL9, CXCL10, and CXCL11. In a mouse model, KRAS-mutated lung adenocarcinoma treated with the combination therapy showed significant tumor growth inhibition compared to PD-1 inhibitor alone. Additionally, the combination therapy significantly enhanced macrophage and CD8+ T cell recruitment. The DEMAND trial confirmed the superior therapeutic efficacy of this combination regimen in patients with KRAS-mutated lung adenocarcinoma. Conclusion: Our study sheds light on the role of RANKL overexpression in promoting immunosuppression and ICI resistance in KRAS-mutated lung adenocarcinoma. Our results indicate that the combination of RANKL inhibitor and PD-1 inhibitor could be a promising therapeutic strategy for this patient subset. Citation Format: Chengming Liu, Hongshuai Li, Sufei Zheng, Nan Sun, Yan Wang, Jie He. Enhanced therapeutic effect of combining denosumab with PD-1 inhibitor in advanced KRAS-mutated lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 656.