Scientists discover how ovarian cancer paralyzes immune cells, paving the way for new therapies

Weill Cornell Medicine researchers have identified a mechanism that ovarian cancer tumors use to disable immune cells, blocking a critical source of energy these cells need to fight cancer. Discovery published in Naturehighlights a new avenue for developing immunotherapy methods against this aggressive and often treatment-resistant cancer.

Ovarian cancer poses significant challenges due to the tumor microenvironment – the complex network of cells, molecules and blood vessels that protect cancer cells from the immune system. In this environment, T cells, which are crucial for mounting an immune response, lose the ability to absorb lipids, the primary source of energy for their functions.

“T cells need lipids as fuel to fight cancer,” said Juan Cubillos-Ruiz, senior author of the study and distinguished professor at Weill Cornell Medicine. “But in the tumor, the mechanisms that control energy supply are disrupted.”

The study showed that although there are large amounts of lipids in ovarian tumors, T cells are unable to use them effectively. The culprit is a protein called fatty acid binding protein 5 (FABP5), which normally helps T cells absorb lipids. However, in the tumor environment, FABP5 becomes trapped inside the cell rather than coming to the surface, preventing lipid uptake and leaving T cells without the energy they need to fight the cancer.

Discovering the cause of immunosuppression

First author Sung-Min Hwang, a postdoctoral researcher in Cubillos-Ruiz’s lab, conducted a study that revealed why FABP5 gets trapped. The team found that a protein called Transgelin 2 is usually responsible for moving FABP5 to the cell surface. However, in ovarian tumors, the production of Transgelin 2 is inhibited by activation of the XBP1 transcription factor, which is triggered by stressful conditions inside the tumor.

“Without Transgelin 2, FABP5 cannot reach the cell surface and T cells cannot access the lipids necessary for energy,” Cubillos-Ruiz explained. This discovery highlights a fundamental way in which ovarian cancers block the immune response, offering new insights into potential treatments.

Progress in ovarian cancer immunotherapy

The study also examined how this mechanism affects CAR T cells, a type of immunotherapy that targets cancer. Although CAR T cells are effective against blood cancers, they have shown limited effectiveness against solid tumors such as ovarian cancer. When tested in mouse models, CAR T cells encountered the same problem as normal T cells – suppression of transgelin 2 and impaired lipid uptake, which prevented them from effectively attacking tumors.

To address this problem, the team developed CAR T cells with a modified version of the Transgelin 2 gene that can bypass tumor suppression mechanisms. This adjustment enabled CAR T cells to absorb lipids and significantly improved their ability to attack ovarian tumors in the models.

“Our findings reveal a key mechanism of immune suppression in ovarian cancer and suggest new strategies to improve T-cell immunotherapy for the treatment of aggressive solid tumors,” Cubillos-Ruiz said.

Implications for future therapies

This study, supported by the National Institutes of Health, the U.S. Department of Defense and other organizations, provides a promising new direction in the treatment of ovarian cancer. Researchers hope to develop more effective immunotherapies for ovarian cancer and other difficult-to-treat solid tumors by understanding and targeting the mechanism by which tumor energy is blocked.

The work also highlights the importance of studying tumor microenvironments and their impact on immune cell function. As research continues, Weill Cornell Medicine aims to translate these findings into new clinical approaches that could improve outcomes for ovarian cancer patients.

FingerLakes1.com is the region’s leading all-digital news publication. The company was founded in 1998 and has been informing residents for over two decades. Got a lead? Send it to (email protected).