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RANKL/PD-1 dual blockade demonstrates survival benefit for patients with advanced lung adenocarcinoma harboring KRAS
Hong-Shuai Li1, Cheng-Ming Liu2, Su-Fei Zheng2
1Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu 610000, China; Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100000, China.
Abstract:
Preclinical/clinical studies suggest that receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) inhibitors combined with immune checkpoint inhibitors (RLICi) enhance anti-tumor efficacy in lung adenocarcinoma (LUAD), yet mechanisms remain unclear. Our retrospective cohort demonstrates RLICi superiority in Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant LUAD. Transcriptomics reveal that RANKL upregulation was inversely correlated with PD-L1 and CXCL9/10/11 levels, suppressing CD8+ T cell infiltration via phosphatidylinositol-3-kinase/AKT serine/threonine kinase-mediated PD-L1 downregulation and macrophage chemokine reduction. In murine models, RLICi outperform PD-1 monotherapy, augmenting M1 macrophage recruitment and CD8+ T cell influx. The prospective DEMAIN trial validates RLICi clinical efficacy. This study elucidates RANKL-driven immunosuppression in KRAS-mutant LUAD and establishes RLICi as a viable therapeutic strategy for this subset. The trial was prospectively registered in the Chinese Clinical Trial Register (registration number: ChiCTR2100047759).
Insights
Receptor activator of nuclear factor κB ligand (RANKL) inhibitors combined with immune checkpoint inhibitors show superior efficacy in KRAS-mutant lung adenocarcinoma. This combination therapy enhances anti-tumor immunity by increasing CD8+ T cell infiltration.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Receptor activator of nuclear factor κB ligand (RANKL) inhibitors combined with immune checkpoint inhibitors (RLICi) show promise in lung adenocarcinoma (LUAD).
- The underlying mechanisms for RLICi efficacy, particularly in KRAS-mutant LUAD, remain largely uncharacterized.
- Understanding these mechanisms is crucial for optimizing therapeutic strategies.
Purpose of the Study:
- To investigate the mechanisms by which RLICi exert anti-tumor effects in KRAS-mutant LUAD.
- To evaluate the efficacy of RLICi compared to PD-1 monotherapy in preclinical models.
- To validate the clinical efficacy of RLICi in a prospective trial.
Main Methods:
- Retrospective analysis of a LUAD cohort treated with RLICi.
- Transcriptomic analysis to identify molecular pathways associated with RLICi response.
- Murine models of LUAD to assess therapeutic efficacy and immune cell infiltration.
- Prospective clinical trial (DEMAIN) to confirm clinical outcomes.
Main Results:
- RLICi demonstrated superior efficacy in KRAS-mutant LUAD compared to historical controls.
- RANKL upregulation was inversely correlated with PD-L1 and CXCL9/10/11, suppressing CD8+ T cell infiltration.
- RLICi enhanced M1 macrophage recruitment and CD8+ T cell influx in murine models.
- The DEMAIN trial confirmed the clinical benefit of RLICi.
Conclusions:
- RANKL plays a critical role in driving immunosuppression within the tumor microenvironment of KRAS-mutant LUAD.
- RLICi effectively overcomes RANKL-mediated immunosuppression, enhancing anti-tumor immune responses.
- RLICi represent a promising therapeutic strategy for patients with KRAS-mutant LUAD.
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