Researchers at Weill Cornell Medicine have identified a method by which ovarian tumors weaken immune cells, specifically T cells, by cutting off their energy supply. This study, published on October 23 in Nature, offers a potential new approach to immunotherapy for treating the aggressive and challenging ovarian cancer.
A major hurdle in treating ovarian cancer lies in the tumor microenvironment—a complex network of cells, molecules, and blood vessels that protects cancer cells from the immune system. In this hostile setting, T cells are unable to absorb lipid molecules, which are crucial for their energy and effective action against tumors.
“T cells rely on lipids for fuel, using them in their mitochondria to fight pathogens and tumors,” said Dr. Juan Cubillos-Ruiz, the study’s senior author and a distinguished associate professor at Weill Cornell Medicine. “However, we still don’t fully understand how this energy supply is controlled.”
How Tumors Block T Cell Energy
While lipids are plentiful in ovarian tumors, T cells cannot utilize them effectively. The research focused on a protein called fatty acid-binding protein 5 (FABP5), which assists in lipid uptake, but its specific location in T cells was unclear. Dr. Sung-Min Hwang, a postdoctoral associate in Dr. Cubillos-Ruiz’s lab, discovered that in tumor samples from patients and mouse models, FABP5 gets trapped in the cytoplasm of T cells instead of moving to the surface to aid lipid absorption.
The team used biochemical assays to identify proteins that interact with FABP5 and found that a protein named Transgelin 2 helps transport FABP5 to the cell surface. They found that ovarian tumors suppress the production of Transgelin 2 in infiltrating T cells. Further investigation revealed that the transcription factor XBP1, activated by stressful tumor conditions, represses the gene responsible for Transgelin 2. This repression traps FABP5 in the cytoplasm, preventing lipid uptake and hindering the T cells’ ability to attack the tumor.
New Immunotherapy Strategies
Armed with this understanding, the researchers explored chimeric antigen receptor T (CAR T) cell therapy. This method involves collecting a patient’s T cells, engineering them to target tumor cells, and reintroducing them into the patient. While CAR T cells have shown success against blood cancers like leukemia and lymphoma, they have struggled with solid tumors, including ovarian cancer.
When the researchers tested CAR T cells in mouse models of metastatic ovarian cancer, they encountered the same issue—repressed Transgelin 2 and impaired lipid uptake. Like normal T cells in the tumor environment, the engineered CAR T cells had FABP5 trapped in the cytoplasm, which limited their effectiveness.
To address this, the researchers introduced a modified gene for Transgelin 2 that could not be repressed by stress factors, ensuring the protein’s expression remained stable. This modification enabled Transgelin 2 to help transport FABP5 to the CAR T cells’ surface, allowing for lipid uptake.
The modified T cells proved significantly more effective at attacking ovarian tumors than the original CAR T cells. “Our findings reveal a key mechanism of immune suppression in ovarian cancer and suggest new strategies to enhance the effectiveness of adoptive T cell immunotherapies for aggressive solid tumors,” said Dr. Cubillos-Ruiz.
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