Related Experiment Video

Updated: Jun 5, 2025

Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
09:40

Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer

Published on: August 2, 2024

2.6K

Interferon response and epigenetic modulation by SMARCA4 mutations drive ovarian tumor immunogenicity

Melica Nourmoussavi Brodeur1, Higinio Dopeso1, Yingjie Zhu1

  • 1Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Science Advances
|December 4, 2024
PubMed

Insights

Loss of SMARCA4 (BRG1) in ovarian cancer boosts tumor immunogenicity by upregulating immune response genes and antigen presentation. This enhances T cell and NK cell activity, suggesting SMARCA4 targeting as an immunotherapy strategy.

Area of Science:

  • Oncology
  • Immunology
  • Genetics

Background:

  • Ovarian cancer (OC) immunogenicity mechanisms are poorly understood.
  • SWI/SNF chromatin remodeling complex mutations, particularly in SMARCA4 (BRG1), correlate with better immune checkpoint blockade response.
  • The underlying mechanisms linking SMARCA4 loss to improved immunotherapy outcomes remain unclear.

Purpose of the Study:

  • To elucidate the cell-intrinsic mechanisms by which SMARCA4 loss influences ovarian cancer immunogenicity.
  • To investigate the role of SMARCA4 in regulating anti-tumor immunity.
  • To explore the potential of targeting SMARCA4 as a therapeutic strategy for ovarian cancer.

Main Methods:

  • Utilized ovarian cancer models with SMARCA4 loss.
  • Analyzed changes in cancer cell-intrinsic immunogenicity, including LTRU, ISGs, and antigen presentation machinery.
  • Investigated the involvement of STING, MAVS, IRF3, and type I interferon receptor signaling pathways.
  • Assessed immune cell infiltration and activation in mouse ovarian and melanoma tumors with SMARCA4 loss.
  • Evaluated the effects of BRG1 inhibitor treatment in SMARCA4-proficient tumor models.

Main Results:

  • SMARCA4 loss in ovarian cancer models increased cell-intrinsic immunogenicity.
  • This included upregulation of long-terminal RNA repeats, interferon-stimulated genes, and antigen presentation machinery.
  • The observed immunogenicity was dependent on STING, MAVS, and IRF3 signaling, but not the type I interferon receptor.
  • Tumors with SMARCA4 loss exhibited increased infiltration and activation of cytotoxic T cells, NK cells, and myeloid cells.
  • BRG1 inhibitor treatment recapitulated these findings in SMARCA4-proficient tumors.

Conclusions:

  • SMARCA4 loss enhances ovarian cancer immunogenicity through intrinsic cellular mechanisms involving STING-MAVS-IRF3 signaling.
  • Targeting SMARCA4 can promote anti-tumor immune responses, including increased cytotoxic T cell and NK cell activity.
  • Modulating chromatin remodeling by targeting SMARCA4 represents a promising strategy to overcome immune evasion in ovarian cancer.

More Related Videos

Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer09:08

Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer

Published on: January 12, 2020

6.7K
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts10:27

Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts

Published on: July 25, 2020

7.2K

Related Concept Videos

Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
5.7K
Tumor Immunotherapy01:27

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
476
Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
3.0K
Tumor Progression02:07

Tumor Progression

Tumor progression is a phenomenon where the pre-formed tumor acquires successive mutations to become clinically more aggressive and malignant. In the 1950s, Foulds first described the stepwise progression of cancer cells through successive stages.
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
6.2K
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
7.3K
Induced Pluripotent Stem Cells01:06

Induced Pluripotent Stem Cells

Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
Somatic...
3.9K