Abstract 4845: The MLL3/GRHL2 complex modulates early malignant development and anti-tumor immunity in upper aerodigestive squamous cell carcinoma

Abstract Upper aerodigestive squamous cell carcinoma (UASCC), including head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC), poses substantial challenges in clinical care due to its aggressive behavior and poorly understood mechanisms of early malignant transformation. This study investigates the role of MLL3 mutations as critical, clonal genomic events driving UASCC tumorigenesis. Using CRISPR-edited organoid models across species, we demonstrate that MLL3 loss facilitates early squamous neoplastic evolution. Additionally, we uncover an MLL3/GRHL2 protein complex that orchestrates epigenomic regulation, particularly influencing immune-related pathways. Strikingly, we identify a novel MLL3/GRHL2-IRF1 axis that induces the expression of Th1 chemokines, such as CXCL9 and CXCL10, enhancing anti-tumor immunity by promoting T cell infiltration within the tumor microenvironment. In syngeneic mouse models, including both subcutaneous and orthotopic settings, MLL3 was shown to modulate the efficacy of immune checkpoint blockade (ICB) therapy. Consistently, clinical data from human patients demonstrate a robust correlation between MLL3 expression and responsiveness to ICB therapy. This study underscores the pivotal role of MLL3 in UASCC pathogenesis and highlights the therapeutic potential of targeting the MLL3/GRHL2-mediated immune response pathways to improve outcomes in UASCC treatment. Citation Format: Chehyun Nam, Guowei Huang, Yueyuan Zheng, Hua Zhao, Ethan Pan, Boyan Hu, Talia Wenger, Hieu Van, Liyan Xu, En-min Li, H.Phillip Koeffler, Kai Ge, Yali Dou, Uttam K. Sinha, Young Min Park, De-Chen Lin. The MLL3/GRHL2 complex modulates early malignant development and anti-tumor immunity in upper aerodigestive squamous cell carcinoma [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 4845.