Fueling the Fight: How Ovarian Tumors Drain T Cell Energy

(Posted on Thursday, October 31, 2024)

Weill Cornell Medicine researchers have discovered a way ovarian tumors cripple immune cells: by tampering with their ability to process energy. This insight could pave the way for new immunotherapies that overcome the hurdles of treating solid tumors—an area where breakthrough treatments like CAR T therapy and checkpoint inhibitors have struggled to succeed.

Powering T Cells to Fight Cancer 

The mitochondria is the powerhouse of the cell—but what happens to a cell when this powerhouse can’t produce enough energy? A cell with an empty tank can’t act or move as it should. This is an underlying dilemma that, in part, makes ovarian cancers so difficult to treat.

All living things require energy; this includes white blood T cells, immune cells that help protect the body against pathogens and cancers. When these cells gather fats, or lipids, from their environment into their molecular powerhouse, they gain the energy needed to recognize and eliminate threats like cancer cells. Additionally, these fats power the T cell as it journeys into the inhospitable tumor environment.

But even though there are ample fats in the ovarian tumor environment, T cells seem unable to access these potential vats of energy. As a result, the T cells can’t fight back. This poorly understood mechanism is one of many ways ovarian cancers thwart the immune system.

How Tumors Tamper with T Cell Energy

To understand what might be going wrong, researchers at Weill Cornell Medicine turned to the tumor microenvironment for clues. This hostile landscape is filled with cells, molecules and blood vessels that actively suppress T cells and prevent them from launching an effective attack against tumors. Something unknown in this environment likely stops T cells from fueling up as they should.

The team took samples of patients’ tumor cells to create mouse ovarian cancer models. Then, they observed how T cells uptake fats in this environment. The experiments discovered that a critical protein for fat uptake called FABP5, or fatty acid-binding protein 5, does not travel to the T cell surface as it should; it remains stuck inside the cell, unable to help the T cell take fats from its surroundings and turn them into energy in the mitochondria.

Why can’t this protein function properly against ovarian tumors? The answer emerged after studying what molecules bind to this fat-uptake protein.

As new research indicates, this fat-uptake protein does not work alone; it relies on another protein called transgelin 2 to transport it to the cell surface. However, the stressful conditions in the ovarian tumor environment alter how specific proteins are made in the T cell. It switches on a protein that represses the gene that produces transgelin 2—in other words, no transgelin 2, no fat uptake. Without this crucial carrier, the fat-uptake protein remains trapped in the T cell, leaving the T cell without enough energy to retaliate against the tumor.

Countering with Immunotherapies 

This key discovery could help develop a more potent and durable generation of cancer immunotherapies.

Consider checkpoint inhibitors, for example. While this therapy has become a standard and first-line treatment for various kinds of cancer, it yields limited benefits for patients with ovarian tumors. This new mechanism may hold answers as to why.

Checkpoint inhibitors work by encouraging the immune system to fight back—this means the T cells, not the drug itself, do the heavy lifting. If ovarian tumors actively prevent T cells from gathering energy as they should, this could explain why the inhibitors have such a limited effect. Developing new strategies to encourage T cells to uptake fats could give checkpoint inhibitors a needed edge against ovarian cancer resistance.

This insight could also benefit CAR T therapy, another revolutionary immunotherapy. With Chimeric Antigen Receptor T cell therapy, a patient’s T cells are collected, genetically modified in a lab, and then injected back into the patient. The edited cells possess a heightened ability to detect and eliminate blood cancer cells in lymphoma, leukemia and multiple myeloma patients but struggle against solid tumors.

But what if the CAR T cells could be altered to withstand the ovarian tumor environment? The researchers at Weill Cornell Medicine attempted to create these upgraded CAR T cells by inserting a modified transgrelin 2 gene into the cells. The modified gene couldn’t be suppressed by the tumor environment and preserved the production of this crucial protein. As a result, these improved CAR T cells proved more effective at eliminating ovarian tumors than normal CAR T cells.

Looking Ahead

Ovarian tumors have proven tough opponents, standing their ground against cutting-edge immunotherapies like CAR T therapy and checkpoint inhibitors. However, new research into how these tumors drain T cell energy may change the game. By enhancing checkpoint inhibitors or designing more resilient CAR T cells, scientists are unlocking fresh ways to outmaneuver solid tumors—one of the toughest challenges in oncology today.