Researchers have identified a way that ovarian tumors weaken immune cells, making it harder for them to fight back. They do this by cutting off the energy supply that T cells rely on. This discovery, published on October 23 in *Nature*, holds promise for a new immunotherapy strategy to tackle ovarian cancer, which is known for being challenging to treat.
At Weill Cornell Medicine, researchers have found a mechanism through which ovarian tumors undermine immune cells and hinder their response by obstructing the energy supply that T cells need. This research, published on October 23 in Nature, suggests a potential new approach to immunotherapy for ovarian cancer, a disease recognized for its aggressiveness and difficulty in treatment.
One major challenge in managing ovarian cancer is the tumor microenvironment—the intricate network of cells, molecules, and blood vessels that protects cancer cells from immune responses. In this adverse setting, T cells struggle to absorb lipid (fat) molecules essential for generating the energy required for a successful attack.
“T cells utilize lipids as energy sources, metabolizing them in their mitochondria to combat pathogens and tumors,” stated Dr. Juan Cubillos-Ruiz, the senior author and a distinguished professor of Infection and Immunology in Obstetrics and Gynecology at Weill Cornell Medicine. “Yet, the detailed mechanisms controlling this crucial energy supply are still not fully understood.”
Understanding Tumor-Induced Energy Blockade in T Cells
While lipids are plentiful in ovarian tumors, T cells appear incapable of using them effectively within this environment. “Our focus has been on a protein known as fatty acid-binding protein 5, or FABP5, which aids in lipid absorption, but we didn’t fully understand its precise location within T cells,” explained Dr. Sung-Min Hwang, a postdoctoral associate who led this study. He found that in tumor specimens from patients and mouse models of ovarian cancer, FABP5 gets stuck in the cytoplasm of T cells instead of relocating to the cell surface, where it would typically facilitate lipid absorption.
“That was the pivotal moment; since FABP5 isn’t reaching the surface, it can’t collect the lipids needed for energy production. However, we still needed to determine why that was happening,” Dr. Cubillos-Ruiz noted, who also co-leads the Cancer Biology Program within the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
Teaming up with collaborators, the researchers conducted various biochemical tests to find proteins that interact with FABP5. They identified a protein named Transgelin 2 that engages with FABP5, aiding its transport to the cell surface.
Further studies revealed that ovarian tumors inhibit the production of Transgelin 2 in infiltrating T cells. Upon deeper investigation, researchers found that the transcription factor XBP1, which is activated by the stressful environment within the tumor, represses the gene responsible for producing Transgelin 2. Without Transgelin 2, FABP5 remains trapped in the cytoplasm of T cells, blocking lipid uptake and rendering the T cells unable to target the tumor.
Creating Targeted Immunotherapies to Combat Tumor Resistance
With the fundamental mechanisms understood, the team investigated an immunotherapy technique called chimeric antigen receptor T (CAR T) cells. This method involves collecting a patient’s T cells, engineering them to fight tumor cells, and then reintroducing these modified cells back into the patient. “While CAR T cells are effective against blood cancers like leukemia and lymphoma, they have not proven successful for solid tumors such as ovarian or pancreatic cancers,” Dr. Cubillos-Ruiz stated.
When Dr. Hwang and his colleagues tested CAR T cells, currently under clinical trial evaluation, in mouse models of metastatic ovarian cancer, they encountered the same issue—Transgelin 2 repression and restricted lipid absorption. Just like the regular T cells in the tumor microenvironment, these engineered CAR T cells had FABP5 trapped in the cytoplasm. As a result, the CAR T cells could not access lipids for energy to effectively target the tumor, underscoring a significant hurdle in applying this immunotherapy to solid tumors like ovarian cancer.
To address this issue, the researchers incorporated a modified Transgelin 2 gene that could not be inhibited by the stress-associated transcription factors, ensuring the production of this vital protein. This modification enabled Transgelin 2 to assist FABP5 in reaching the surface of the CAR T cells, allowing for lipid absorption.
As a result, these enhanced T cells were significantly more effective at combating ovarian tumors compared to the standard CAR T cells. “Our research uncovers a crucial mechanism of immune suppression in ovarian cancer and paves the way for improving the effectiveness of adoptive T cell therapies in aggressive solid tumors,” concluded Dr. Cubillos-Ruiz.
