Weill Cornell Medicine researchers have identified a mechanism that ovarian cancer tumors use to disable immune cells, blocking a critical energy supply that these cells need to fight off cancer. The discovery, published in Nature, highlights a new avenue for developing immunotherapy treatments against this aggressive and often treatment-resistant cancer.
Ovarian cancer presents significant challenges due to its 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 function.
“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 research identified that although lipids are abundant within ovarian tumors, T cells cannot utilize them effectively. The culprit is a protein called fatty acid-binding protein 5 (FABP5), which normally helps T cells absorb lipids. In the tumor environment, however, FABP5 becomes trapped inside the cell rather than moving to the surface, preventing lipid uptake and leaving the T cells without the necessary energy to fight the tumor.
Discovering the cause of immune suppression
First author Sung-Min Hwang, a postdoctoral associate in Cubillos-Ruiz’s lab, led the study that uncovered why FABP5 becomes trapped. The team discovered that a protein called Transgelin 2 is typically responsible for moving FABP5 to the cell surface. In ovarian tumors, however, the production of Transgelin 2 is suppressed due to the activation of the transcription factor XBP1, which is triggered by the stressful conditions inside the tumor.
“Without Transgelin 2, FABP5 cannot get to the cell surface, and T cells cannot access the lipids they need for energy,” explained Cubillos-Ruiz. This discovery highlights a fundamental way that ovarian tumors block the immune response, offering new insights for potential treatments.
Advancing immunotherapy for ovarian cancer
The research also explored how this mechanism affects CAR T cells, a type of immunotherapy designed to target tumors. While CAR T cells are effective against blood cancers, they have shown limited success with solid tumors like ovarian cancer. When tested in mouse models, CAR T cells encountered the same problem as normal T cells—Transgelin 2 suppression and impaired lipid uptake, which left them unable to attack the tumors effectively.
To address this issue, the team engineered CAR T cells with a modified version of the Transgelin 2 gene that could bypass the tumor’s suppression 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 a key mechanism of immune suppression in ovarian cancer and suggest new strategies to enhance T cell immunotherapies for treating aggressive solid tumors,” Cubillos-Ruiz said.
Implications for future treatments
This study, supported by the National Institutes of Health, the U.S. Department of Defense, and other organizations, offers a promising new direction for ovarian cancer treatment. 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 underscores the importance of investigating tumor microenvironments and their impact on immune cell function. As the research continues, Weill Cornell Medicine aims to translate these findings into new clinical approaches that could improve outcomes for patients with ovarian cancer.
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