Mutation of SMARCA4 Induces Cancer Cell-Intrinsic Defects in the Enhancer Landscape and Resistance to Immunotherapy

Authors

Yawen Wang
Ismail M Meraz
Md Qudratullah
Sasikumar Kotagiri
Yanyan Han
Yuanxin Xi
Jing Wang
Kadir C Akdemir
Jack A Roth
Yonathan Lissanu

Publication Date

6-2-2025

Journal

Cancer Research

DOI

10.1158/0008-5472.CAN-24-2054

PMID

40080526

PMCID

PMC12127800

PubMedCentral® Posted Date

3-13-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Cancer genomic studies have identified frequent alterations in genes encoding components of the SWI/SNF chromatin remodeling complex, including SMARCA4 and ARID1A. Importantly, clinical reports indicate that SMARCA4-mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. In this study, we corroborated the clinical findings by using immune-humanized, syngeneic, and genetically engineered mouse models of lung cancer harboring SMARCA4 deficiency. Specifically, models with SMARCA4 loss showed decreased response to anti-PD-1 immunotherapy associated with significantly reduced infiltration of dendritic cells and CD4+ T cells into the tumor microenvironment. SMARCA4 loss in tumor cells led to profound downregulation of STING1, IL1β, and other components of the innate immune system, as well as inflammatory cytokines that are required for efficient recruitment and activity of immune cells. The deregulation of gene expression was caused by cancer cell-intrinsic reprogramming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in innate immune response, such as STING1, IL1β, type I IFN, and inflammatory cytokines. Interestingly, the transcription factor NF-κB-binding motif was enriched in enhancers that lose accessibility upon SMARCA4 deficiency. Furthermore, SMARCA4 and NF-κB co-occupied the same genomic loci on enhancers associated with STING1 and IFNβ, indicating a functional interplay between SMARCA4 and NF-κB. Taken together, these findings provide the mechanistic basis for the poor response of SMARCA4-mutant tumors to immunotherapy and establish a functional link between SMARCA4 and NF-κB in innate immune and inflammatory gene expression regulation. Significance: Epigenetic reprogramming in SMARCA4-mutant cancer cells alters immune infiltration and limits immunotherapy efficacy by downregulating immunostimulatory gene expression, which could potentially be targeted to overcome immunotherapy resistance in SMARCA4-deficient tumors.

Keywords

Animals, Transcription Factors, Mice, Humans, Nuclear Proteins, DNA Helicases, Mutation, Immunotherapy, Tumor Microenvironment, Lung Neoplasms, Drug Resistance, Neoplasm, Enhancer Elements, Genetic, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Immunity, Innate, Immune Checkpoint Inhibitors

Published Open-Access

yes

Recommended Citation

Wang, Yawen; Meraz, Ismail M; Qudratullah, Md; et al., "Mutation of SMARCA4 Induces Cancer Cell-Intrinsic Defects in the Enhancer Landscape and Resistance to Immunotherapy" (2025). Faculty, Staff and Student Publications. 83.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/83