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Investigators Identify Gene That Prevents Immune Response in Ovarian Cancer

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Key Points

  • Dendritic cells in the tumor microenvironment exhibit endoplasmic reticulum stress and robust XBP1 activation, which drives primary and metastatic ovarian cancer progression.
  • Silencing XBP1 in dendritic cells extends host survival by enhancing T-cell antitumor immunity.
  • Relieving endoplasmic reticulum stress in immune cells may offer a new approach to cancer immunotherapy.

Researchers have identified a gene in dendritic cells that disables an effective immune response against ovarian cancer tumors. In preclinical studies, the researchers found that silencing this gene, XBP1, in dendritic cells restores their function and enhances T-cell antitumor immunity. XBP1 is part of the endoplasmic reticulum stress response pathway. According to the study, targeting the endoplasmic reticulum stress response should concomitantly inhibit tumor growth and enhance anticancer immunity, possibly offering a unique approach to cancer immunotherapy for ovarian cancer. The study by Cubillos-Ruiz et al was published in Cell.

Study Methodology

The researchers analyzed stage III and IV human ovarian cancer tumor specimens and ovarian cancer tumor samples from mice and sought to determine whether XBP1 might drive tumor growth by inhibiting dendritic cells (DCs)-dependent anticancer immunity.

Study Findings

The researchers found that dendritic cells in the tumor microenvironment exhibit endoplasmic reticulum stress and robust XBP1 activation, producing a buildup of lipid molecules within the dendritic cells. XBP1 also "switched on" genes that block their ability to stimulate other immune cells. As a result, “DC-specific XBP1 deletion or selective nanoparticle-mediated XBP1 silencing in DCs restored their immunostimulatory activity in situ and extended survival by evoking protective type 1 antitumor responses.”

The researchers concluded, “Targeting the endoplasmic reticulum stress response should concomitantly inhibit tumor growth and enhance anticancer immunity, thus offering a unique approach to cancer immunotherapy.”

“Immune-based approaches have succeeded in other lethal cancers, such as melanoma, and it may be very beneficial as well in ovarian cancer,” said Laurie H. Glimcher, MD, senior author of the study and the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College in New York, in a statement. “Our study shows that XBP1 activation in dendritic cells drives both the primary and metastatic ovarian cancer progression. We believe that targeting XBP1 should both inhibit tumor growth and enhance anticancer immunity.”

Dr. Glimcher, the corresponding author of this study, holds equity in and is on the Board of Directors of Bristol-Myers-Squibb.

Funding for this study was provided by the National Institutes of Health, Irvington Institute Fellowship Program of the Cancer Research Institute, and Fundación Alfonso Martin Escudero.

 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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