Ovarian cancer, a notorious adversary in the realm of oncology, has long been known for its aggressiveness and the challenges it poses to treatment. In recent research published on October 23 in Nature, a team from Weill Cornell Medicine reveals how ovarian cancer cripples immune cells, blocking their ability to mount a sustained attack on tumors. This study sheds light on an essential biological mechanism by which ovarian tumors disrupt the energy supply T cells rely on, marking a promising step toward developing more effective immunotherapies.
Ovarian Cancer and the Challenge of Immune Suppression
Treating ovarian cancer has remained challenging due to the tumor’s complex environment, called the tumor microenvironment. This hostile area is populated by a mix of cells, molecules, and blood vessels that essentially shield the cancerous cells from the body’s immune system. Within this environment, T cells—the body’s primary soldiers against infections and tumors—lose their ability to harness the energy they need for combat.
According to senior author Dr. Juan Cubillos-Ruiz, Distinguished Associate Professor of Infection and Immunology at Weill Cornell Medicine, “T cells rely on lipids as fuel, burning them in their mitochondria to power their fight against pathogens and tumors. However, the molecular mechanisms governing this critical energy supply remain poorly understood.”
This groundbreaking study identifies how ovarian tumors prevent T cells from utilizing lipids for energy, providing critical insights into the underlying mechanisms of immune suppression in ovarian cancer.
Key Findings: T Cell Energy Supply and Lipid Blockage
Lipids, or fat molecules, are present in abundance within ovarian tumors, but surprisingly, T cells within the tumor environment seem unable to access these lipids as a source of fuel. Central to this mechanism is a protein called fatty acid-binding protein 5 (FABP5), which plays a critical role in lipid uptake.
Lead researcher Dr. Sung-Min Hwang, a postdoctoral associate in Dr. Cubillos-Ruiz’s lab, found that FABP5 becomes trapped in the cytoplasm of T cells instead of moving to the cell surface. This misplacement prevents the protein from assisting in lipid uptake from the surrounding environment, thereby starving the T cells of the necessary fuel to launch an attack on the tumor.
“When FABP5 isn’t reaching the surface, it cannot bring in the essential lipids for energy production,” explained Dr. Cubillos-Ruiz. This insight led the researchers to question why FABP5 was unable to reach the cell surface and what factors were interfering with its function.
The Role of Transgelin 2 and Tumor Suppression
To further investigate, the research team conducted a series of biochemical tests and identified a protein called Transgelin 2 that binds with FABP5 and enables its transport to the cell surface. The presence of Transgelin 2 ensures that T cells can utilize lipids, giving them the energy to perform their tumor-fighting functions. However, in ovarian tumors, Transgelin 2 production is notably suppressed in T cells that have infiltrated the tumor microenvironment.
This suppression occurs due to a transcription factor known as XBP1, which is activated by the intense conditions within the tumor environment. XBP1 represses the gene responsible for producing Transgelin 2, thus trapping FABP5 in the cytoplasm of T cells and hindering their capacity to fight the tumor.
This discovery of how ovarian tumors restrict T cell access to lipids by limiting Transgelin 2 production is monumental. By better understanding this interaction, scientists can explore innovative therapies to restore T cell functionality within the tumor environment.
Redesigning Immunotherapy with CAR T Cells to Overcome Tumor Defenses
With these insights, the researchers explored a potential solution using CAR T cell therapy, an advanced form of immunotherapy. CAR T cells are engineered to recognize and attack specific tumor cells. While CAR T cells have shown effectiveness in treating blood cancers such as leukemia and lymphoma, they face significant obstacles in treating solid tumors like ovarian cancer.
When the researchers tested CAR T cells on mouse models of ovarian cancer, they observed similar issues—Transgelin 2 was repressed, preventing FABP5 from reaching the cell surface. This discovery highlighted a key limitation in CAR T cell therapy for solid tumors, as the T cells still faced the same lipid uptake restriction as natural T cells within the tumor microenvironment.
In response to this obstacle, the research team designed a modified CAR T cell with a specially engineered Transgelin 2 gene that resists suppression by XBP1. This modification allowed Transgelin 2 to continue guiding FABP5 to the cell surface, where it could access the essential lipids for energy production.
Enhanced T Cell Efficacy Against Ovarian Tumors
The modified CAR T cells demonstrated far greater effectiveness in fighting ovarian tumors than the original CAR T cells. By restoring the lipid uptake capacity, these engineered cells had the energy required to sustain their attack on the cancerous cells, offering a promising avenue for improving immunotherapy for ovarian cancer.
The study not only illuminates a significant mechanism of immune suppression within ovarian cancer but also suggests novel strategies for enhancing the potency of adoptive T cell therapies for aggressive solid tumors. This approach may prove transformative for treating cancers traditionally resistant to immune-based treatments.
Dr. Cubillos-Ruiz emphasized the potential impact of this discovery, noting, “Our findings reveal a key mechanism of immune suppression in ovarian cancer and open new avenues to improve adoptive T cell immunotherapies in aggressive solid malignancies.”
The Future of Immunotherapy for Ovarian Cancer
By uncovering the mechanisms that ovarian tumors use to suppress T cell activity, this research highlights the potential for engineered immunotherapies to better penetrate and disrupt the tumor microenvironment. Scientists hope that with further refinement, CAR T cells and other immunotherapies could target solid tumors more effectively, marking a significant step forward in the fight against ovarian cancer.
This study, led by Weill Cornell Medicine, provides a clearer understanding of how the tumor microenvironment disables the body’s natural defense system. By addressing the fundamental issue of energy suppression in T cells, these findings lay the groundwork for future therapies that might overcome the defense mechanisms used by ovarian cancer and similar malignancies.