The MLL3/GRHL2 Complex Regulates Malignant Transformation and Anti-tumor Immunity in Squamous Cancer

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2025 Feb 18

PMID 39964485

Authors

Chehyun Nam

Guowei Huang

Yueyuan Zheng

Hua Zhao

Yuhao Pan

Boyan Hu

Talia Wenger

Hieu T Van

Li-Yan Xu

En-Min Li

H Phillip Koeffler

Kai Ge

Yali Dou

Uttam K Sinha

Young Min Park

De-Chen Lin

Affiliations

Soon will be listed here.

Abstract

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.

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