Researchers discover how ovarian cancer paralyzes immune cells, paving the way for new treatments

Researchers at Weill Cornell Medicine have identified a mechanism that ovarian cancer tumors use to disable immune cells, blocking a crucial energy supply that these cells need to fight cancer. The discovery, published in Naturehighlights a new avenue for developing immunotherapy treatments against this aggressive and often treatment-resistant cancer.

Ovarian cancer poses significant challenges due to the tumor microenvironment: a 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 their ability to absorb lipids, an essential energy source for their functioning.

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

The study found that although lipids are abundant in ovarian tumors, T cells cannot 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 within the cell instead of moving to the surface, preventing lipid uptake and leaving the T cells without the necessary energy to fight the tumor.

Discovering the cause of immunosuppression

First author Sung-Min Hwang, a postdoctoral fellow in Cubillos-Ruiz’s lab, led the study that uncovered why FABP5 gets stuck. The team discovered that a protein called Transgelin 2 is typically responsible for moving FABP5 to the cell surface. However, in ovarian tumors, Transgelin 2 production is suppressed due to the activation of the transcription factor XBP1, which is induced by the stressful conditions in the tumor.

“Without Transgelin 2, FABP5 cannot reach the cell surface and T cells cannot access the lipids they need for energy,” explains Cubillos-Ruiz. This discovery highlights a fundamental way in which ovarian tumors block the immune response, providing new insights for potential treatments.

Promotion of immunotherapy for ovarian cancer

The study also examined how this mechanism affects CAR T cells, a type of immunotherapy designed to target tumors. Although CAR T cells are effective against blood cancers, they have shown limited success against solid tumors such as ovarian cancer. When tested in mouse models, CAR T cells encountered the same problem as normal T cells: Transgelin 2 suppression and reduced lipid uptake, preventing them from effectively attacking tumors.

To address this problem, the team developed CAR T cells with a modified version of the Transgelin 2 gene, which could bypass the tumor’s suppressor mechanisms. This adjustment allowed the CAR T cells to absorb lipids and significantly improved their ability to attack ovarian tumors in the models.

“Our findings reveal an important mechanism of immunosuppression in ovarian cancer and suggest new strategies to improve T-cell immunotherapies for the treatment of aggressive solid tumors,” said Cubillos-Ruiz.

Implications for future treatments

This study, supported by the National Institutes of Health, the US Department of Defense and other organizations, offers a promising new direction for the treatment of ovarian cancer. By understanding and targeting the tumor’s energy-blocking mechanism, researchers hope to develop more effective immunotherapies for ovarian cancer and other difficult-to-treat solid tumors.

The work also underlines the importance of investigating 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 can improve outcomes for patients with ovarian cancer.

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