Researchers Identify Mechanism of Immune Suppression in Ovarian Cancer

Researchers at Weill Cornell Medicine have shown that ovarian cancers disable immune cells and prevent them from attacking by cutting off the energy source that T cells rely on. The study, which was published in the journal Nature, suggested a promising new immunotherapy strategy for ovarian cancer, a disease that is infamously aggressive and challenging to treat.

The tumor microenvironment, a complex ecosystem of cells, chemicals, and blood vessels that protects cancer cells from the immune system, is a major treatment challenge for ovarian cancer. In this hostile environment, T cells are unable to absorb the lipid (fat) molecules required for energy to launch a successful attack.

T cells rely on lipids as fuel, burning them in their mitochondria to power their fight against pathogens and tumors. However, the molecular mechanisms that govern this critical energy supply are still not well understood.”

Dr. Juan Cubillos-Ruiz, The William J. Ledger, M.D., Distinguished Associate Professor and Study Senior Author, Weill Cornell Medicine

Identifying How Tumors Block T-Cell Energy Supply

Ovarian cancers contain a lot of lipids, but T cells do not seem to be able to use them in this setting.

Researchers have focused on a protein called fatty acid-binding protein 5, or FABP5, which facilitates lipid uptake, but its exact location within the T cell remained unclear.”

Dr. Sung-Min Hwang, Study Lead and Postdoctoral Associate, Weill Cornell Medicine

Dr. Hwang found that rather than traveling to the cell surface, where it would typically aid in absorbing lipids from the environment, FABP5 gets stuck inside the cytoplasm of T cells in patient-derived tumor specimens and animal models of ovarian cancer.

“That was the ‘aha!’ moment; since FABP5 is not getting to the surface, it couldn’t bring in the lipids necessary for energy production. But we still needed to figure out why,” said Dr. Cubillos-Ruiz, who is also co-leader of the Cancer Biology Program in the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

Together with partners, the researchers identified proteins that bind to FABP5 using a variety of biochemical experiments. They discovered that FABP5 interacts with a protein called Transgelin 2, which facilitates its movement to the cell surface.

Subsequent research showed that ovarian cancers inhibit invading T lymphocytes' ability to produce Transgelin 2. Further investigation revealed that the gene encoding Transgelin 2 is repressed by the transcription factor XBP1, which is triggered by the stressful conditions inside the tumor. FABP5 is stuck in the cytoplasm of T cells in the absence of Transgelin 2, which inhibits lipid uptake and makes it impossible for the T cells to assault the tumor.

Designer Immunotherapies to Overcome Tumor Defenses

After figuring out this basic mechanism, the group investigated chimeric antigen receptor T (CAR T) cells as an immunotherapy. This method gathers a patient's T cells, modifies them to target tumor cells, and then injects the patient with the designer cells.

 “CAR T cells work well against hematological cancers like leukemia and lymphoma, but they are really not effective for solid tumors like ovarian or pancreatic cancers,” Dr. Cubillos-Ruiz said.

Dr. Hwang and his colleagues discovered the same issue Transgelin 2 suppression and poor lipid uptake—when they tried CAR T cells, which are presently undergoing clinical trials, in mouse models of metastatic ovarian cancer.

FABP5 was entangled in the cytoplasm of the modified CAR T cells, just like it was in the cytoplasm of healthy T cells in the tumor microenvironment. This highlighted a crucial obstacle in applying this immunotherapy for solid tumors like ovarian cancer since the CAR T cells could not access lipids for energy to attack the tumor efficiently.

The researchers fixed the issue by inserting a modified Transgelin 2 gene, which prevented stress transcription factors from blocking it and maintained the expression of the vital protein. This made it possible for Transgelin 2 to chaperone FABP5 to the CAR T cell surface so that it could absorb lipids.

Compared to the original CAR T cells, the improved T cells were significantly more successful in combating ovarian cancers.

Our findings reveal a key mechanism of immune suppression in ovarian cancer and suggest new avenues to improve the efficacy of adoptive T cell immunotherapies in aggressive solid malignancies.”

Dr. Juan Cubillos-Ruiz, The William J. Ledger, M.D., Distinguished Associate Professor and Study Senior Author, Weill Cornell Medicine