Weill Cornell Medicine researchers have identified a key factor that weakens the immune response in ovarian cancer, providing potential new avenues for treatment.
A team from Weill Cornell Medicine has uncovered how ovarian tumors impair immune cells, particularly T cells, from attacking cancer effectively. The study, published on October 23 in Nature, reveals that the tumors block T cells’ access to energy, which is crucial for their function. This discovery opens the door for new immunotherapy approaches to combat ovarian cancer, a disease known for its aggressive nature and resistance to current treatments.
T cells play a critical role in the immune system by attacking pathogens and tumors. To function effectively, they rely on lipids as a source of energy. In ovarian tumors, however, T cells are unable to take up these essential lipids, rendering them ineffective. “T cells burn lipids in their mitochondria to fuel their fight against cancer,” explained Dr. Juan Cubillos-Ruiz, the study’s senior author. However, the underlying mechanisms that disrupt this energy supply in the tumor environment were previously not well understood.
The Role of Lipid Uptake Blockage in T Cells
While lipids are plentiful in ovarian tumors, T cells in the tumor environment are unable to use them for energy. Researchers focused on fatty acid-binding protein 5 (FABP5), a key protein that facilitates lipid uptake in T cells. In normal conditions, FABP5 moves to the cell surface to enable lipid absorption, but the study found that, in ovarian tumors, it gets trapped inside the T cell cytoplasm, preventing lipid uptake.
Dr. Sung-Min Hwang, a postdoctoral associate and the study’s lead author, discovered that this blockage was caused by the repression of another protein, Transgelin 2, which is essential for moving FABP5 to the cell surface. The research revealed that within the stressful tumor microenvironment, a transcription factor called XBP1 suppresses the gene responsible for producing Transgelin 2. This suppression leads to FABP5 being trapped inside T cells, making them unable to access the lipids they need for energy, ultimately hindering their ability to attack the tumor.
Immunotherapy Approaches to Overcome Tumor Defenses
In light of this discovery, the research team explored a potential solution using chimeric antigen receptor (CAR) T cell therapy. This immunotherapy technique modifies a patient’s T cells to target cancer cells before reintroducing them into the patient. While CAR T cells have shown success in treating blood cancers like leukemia and lymphoma, they have not been as effective against solid tumors such as ovarian cancer.
When the researchers tested CAR T cells in mouse models of ovarian cancer, they encountered the same issue—Transgelin 2 repression led to FABP5 being trapped in the cytoplasm, preventing the CAR T cells from accessing lipids for energy. To address this, the researchers inserted a modified version of the Transgelin 2 gene, ensuring its expression despite the stress factors in the tumor. This modification allowed FABP5 to move to the cell surface and take up lipids, restoring the T cells’ ability to attack the tumor effectively.
The enhanced CAR T cells demonstrated significantly improved tumor-fighting capabilities in ovarian cancer models. “Our findings reveal a key mechanism of immune suppression in ovarian cancer and suggest new avenues to improve the efficacy of T cell immunotherapies in aggressive solid tumors,” concluded Dr. Cubillos-Ruiz.
This breakthrough in understanding how ovarian tumors block the immune system offers hope for more effective treatments in the future, particularly for solid malignancies like ovarian cancer.
