Researchers Explore Immunotherapy With XBP1 Inhibition in Ovarian Cancer

Laurie H. Glimcher, MD

In preclinical studies, researchers at Weill Cornell Medical College have demonstrated that turning off the gene XBP1 restores dendritic cell function and could trigger robust immune responses against ovarian tumors, according to a recent article published in Cell.

The gene is part of the endoplasmic reticulum stress response pathway—also known as the unfolded protein response—that can allow tumors to grow and survive when they are deprived of nutrients and oxygen.

Investigators at Weill Cornell reported last year that the gene plays a key role in the development and progression of triple-negative breast cancer. Because of XBP1’s ability to promote tumor cell survival, the group suspected it could also play a role as an inhibitor of antitumor immunity.

In the study, researchers tested a strategy in which mice were injected with nanoparticles. Dendritic cells detect the nanoparticles as invaders and ingest them. Once inside, nanoparticles deliver the molecule that turns XBP1 off, allowing dendritic cells to tell the immune system to attack the cancer. Researchers are working on developing first-in-class drugs that could inhibit the activity of XBP1 in cancer cells and dendritic cells.

To better understand the impact of these findings and next steps in the research, OncLive spoke with senior author Laurie H. Glimcher, MD, Stephen and Suzanne Weiss Dean of Weill Cornell Medical College and a researcher at the Sandra and Edward Meyer Cancer Center.

OncLive: What are the biggest challenges in treating ovarian cancer?

Dr Glimcher: Ovarian cancer has long been known as a silent killer because, for the most common form of the disease, symptoms and diagnosis usually occur only at an advanced stage when treatment is rarely curative. Many researchers are looking at ways to screen for early ovarian cancer, whether it is with a biomarker or scan.

Standard treatment goes only so far. Ninety percent of patients have a recurrence, which indicates the tumors are not responding in a meaningful way to repeated bouts of chemotherapy and surgery. That has led to more aggressive surgery, chemotherapy, radiotherapy, and surveillance.

However, we also now know that ovarian cancers are very heterogeneous—they come in many molecular subtypes, even subtypes within subtypes, and low-grade versus high-grade tumors. This suggests that there are a number of molecular drivers that could be targeted from the pipeline of drugs that exist or are being tested for a number of cancers.

What role does XBP1 play in ovarian cancer?

XBP1 is a bad actor, responsible for driving both primary and metastatic ovarian cancer progression. It contributes to creating the highly immunosuppressive tumor microenvironment that is very prominent in some cancers, including ovarian cancer.

XBP1 shuts off the ability of the immune system to fight ovarian cancer, thus promoting tumor cell survival. We found that it specifically switches genes in dendritic cells that allow these innate immune cells to activate T lymphocytes, the key immune cells that are required to kill ovarian cancer cells. Dendritic cells are the immune system’s early warning system, so shutting them down means the tumors are free to grow unhindered by natural immunity.

When was it first discovered?

My team identified XBP1 and published this finding in 1990 in Science. This study is the first time XBP1 has been found to co-opt and turn off immune cell function in cancer.

What impact could a better understanding of XBP1 have on the treatment of ovarian cancer?

We believe a drug that inhibits XBP1 or more likely its upstream activator, the ER stress enzyme IRE1a, could give ovarian patients the ability to fight their disease using their own natural defenses for the first time. XBP1 is active at all stages of ovarian cancer, meaning that the immune system is quiescent. Our study demonstrates that it is possible to turn XBP1 off in ovarian cancer cells.

What are the next steps in determining novel therapies that could inhibit the activity of XBP1?

We are now devising first-in-class drugs that can inhibit the activity of XBP1 in cancer cells and dendritic cells, which would both sensitize the cancer to treatment and restore an immune response against it. We have already shown, in this study, that it is possible to turn XBP1 off in ovarian cancer, allowing dendritic cells to tell the immune system to attack the cancer.

Do you see immunotherapy playing a bigger role in ovarian cancer in the future?

Certainly. We think XBP1, which turns off immune function, is ovarian cancer’s Achilles heel. A drug that restores that immune attack would be considered immunotherapy.

The field of immunotherapy is rapidly advancing. Immune-based approaches have succeeded in other lethal cancers, such as melanoma, and we believe targeting IRE1a or XBP1 could offer another breakthrough in a deadly cancer.

Cubillos-Ruiz J, Silberman P, Rutkowski M. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. [published online June 11, 2015]. Cell. doi: http://dx.doi.org/10.1016/j.cell.2015.05.025.