The MLL3/GRHL2 complex regulates malignant transformation and anti-tumor immunity in squamous cancer
Upper aerodigestive squamous cell carcinoma (UASCC) presents significant challenges in clinical management due to its aggressive nature. Here, we elucidate the role of MLL3 mutations as early, clonal genomic events in UASCC tumorigenesis, highlighting their role as foundational drivers of cancer development. Utilizing CRISPR-edited, cross-species organoid modeling, we demonstrate that loss of MLL3 contributes to early squamous neoplastic evolution. Furthermore, we identify an MLL3/GRHL2 protein complex that regulates the UASCC epigenome, particularly impacting immune response pathways. Notably, a novel MLL3/GRHL2-IRF1 axis promotes the expression of Th1 chemokines, enhancing anti-tumor immunity by facilitating T cell infiltration into the tumor microenvironment. Consequently, MLL3 regulates the in vivo efficacy of immune checkpoint blockade (ICB) therapy, corroborated by the strong association between MLL3 expression and human patients' clinical response to ICB therapy. Our work underscores the significance of MLL3 in UASCC pathogenesis and highlights the interplay between MLL3/GRHL2 and immune response pathways as potential therapeutic targets for UASCC treatment.
Authors
- De‐Chen Lin (ORCID: https://orcid.org/0000-0002-1951-367X)
- Kai Ge (ORCID: https://orcid.org/0000-0002-7442-5138)
- Li‐Yan Xu (ORCID: https://orcid.org/0000-0002-1618-4292)
- Guowei Huang
- Hieu T. Van (ORCID: https://orcid.org/0000-0002-3328-915X)
- En‐Min Li (ORCID: https://orcid.org/0000-0001-6375-3614)
- Yueyuan Zheng (ORCID: https://orcid.org/0000-0002-5692-8903)
- Chehyun Nam (ORCID: https://orcid.org/0000-0001-8604-2313)
- Talia A. Wenger (ORCID: https://orcid.org/0000-0001-6616-2780)
- Yali Dou (ORCID: https://orcid.org/0000-0002-4040-1429)
- H. Phillip Koeffler (ORCID: https://orcid.org/0000-0001-5839-9913)
- Hua Zhao (ORCID: https://orcid.org/0000-0001-7148-547X)
- Young Min Park (ORCID: https://orcid.org/0000-0002-7593-8461)
- Uttam K. Sinha (ORCID: https://orcid.org/0000-0003-4208-8904)
- Boyan Hu
- Y. Pan (ORCID: https://orcid.org/0000-0002-0812-9007)
Institutions
- University of Southern California (US)
- Cedars-Sinai Medical Center (US)
- National Institutes of Health (US)
- Yonsei University (KR)
- Shantou University (CN)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- Shantou University Medical College (CN)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-02-18
- DOI
- https://doi.org/10.1084/jem.20240758
- Citations
- 3
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- Concern Foundation
- Natural Science Foundation of Guangdong Province
- National Institutes of Health
- National Cancer Institute