Lipid metabolism helps T cells fight solid cancers

Insights into the mechanism that ovarian cancer uses to suppress immune cells may offer a promising immunotherapy approach for ovarian cancer and other solid malignancies.

In a recent study, researchers at Weil Cornell Medicine (NY, USA) used a collection of biochemical assays to gain insights into the mechanisms involved in ovarian cancer’s ability to suppress the immune system, specifically, how solid tumors affect the function of T cells. By improving our understanding of the intricacies of these mechanisms, these findings could offer novel approaches towards improving cancer T cell immunotherapies.

A patient’s T cells can be engineered into chimeric antigen receptor (CAR) T cells to attack tumor cells; this type of immunotherapy is often used to treat hematological cancers such as leukemia. However, for solid tumors like ovarian cancer, CAR T has been ineffective. Ovarian cancer is aggressive and difficult to treat, in part due to the complex environment of cells, molecules and blood vessels that guard cancer cells from the immune system. This environment impacts the effectiveness of T cells, severely limiting their ability to uptake lipid fat molecules, which give them energy to attack cancer cells.

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Interestingly, lipids are abundant in ovarian cancer, yet T cells seem unable to utilize them. Researchers have been trying to help T cells uptake lipids by focusing on a fatty acid-binding protein 5 (FABP5), however, its location in the T cells remained unclear – until Sung-Min Hwang, who led the study, discovered something monumental: FABP5 was trapped.

From patient-derived tumor specimens and mouse models of ovarian cancer, Hwang discovered that FABP5 was stuck in the cytoplasm of the T cells and was, therefore, unable to move toward the cell surface to uptake the lipids needed for energy. This discovery was just the start of their journey as they still couldn’t understand why FABP5 couldn’t move towards the surface of the T cells.

The researchers decided to work with collaborators, employing a collection of biochemical assays to identify proteins that interact with FABP5. In doing so, they discovered that Transgelin 2, a cytoskeleton organizer, interacts with FABP5 and helps move it to the cell surface. Furthermore, they discovered that the transcription factor XBP1, which is activated by the stressful conditions within the tumor microenvironment, prevented the gene encoding Transgelin 2 from being expressed. Without Transgelin 2, FABP5 gets trapped in the cytoplasm of T cells, preventing lipid uptake and rendering the T cells unable to attack the tumor.

With Transgelin 2 being a key component in the mechanism of lipid uptake for T cells, the team assessed CAR-T cells in mouse models of metastatic ovarian cancer to further understand why CAR-T therapy was not effective in treating solid cancers. They found the same thing – FABP5 was also stuck in the cytoplasm of the engineered CAR-T cells because of the transcription factor XBPI.

To combat this, the researchers then inserted a modified Transgelin 2 gene that could bypass stress transcription factors, allowing Transgelin 2 to facilitate FABP5 to the surface of the CAR-T cells to uptake lipids. Remarkably, the enhanced T cells were able to more effectively attack the ovarian cancer tumors when compared to the original CAR-T cells.

“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,” commented Juan Cubillos-Ruiz, co-leader of the Cancer Biology Program at Weill Cornell Medicine.