The uterus, ovaries, and fallopian tubes sit on top of a pink background.

Ovarian cancers are notoriously difficult to treat.

Credit: iStock.com/Elena Nechaeva

Boosting ovarian cancer immunotherapy with fatty acid uptake

Ovarian tumors are extremely difficult to get rid of. Scientists are figuring out how to leverage the immune system to help.
Maggie Chen Headshot
| 3 min read
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Ovarian cancer is notoriously hard to treat — particularly metastatic ovarian cancer, which is often resistant to the standard treatments of surgical removal and chemotherapy. Even when the ovaries are completely removed, cancerous cells can remain and wreak havoc on the body.

Among other reasons, ovarian cancer is dangerous because it transforms the body’s immune system into a dysfunctional mess. “There’s this idea of a hostile microenvironment in ovarian cancer,” said Roddy O’Connor, an immunologist at the University of Pennsylvania. The body’s T cells in the region near the tumor lose their normal capabilities of bumping up the immune response and killing cancerous cells. 

There’s this idea of a hostile microenvironment in ovarian cancer.
- Roddy O’Connor, University of Pennsylvania

Now, scientists at Weill Cornell Medicine have discovered that this happens because a certain molecular pathway responsible for fat trafficking becomes dysregulated in T cells during ovarian cancer (1). They designed a therapy to target this pathway and found that it improved elimination of metastatic ovarian cancers. These findings, the authors say, could help develop next-generation immunotherapies that more effectively target these tricky cancers. 

Juan Cubillos-Ruiz, an immunologist at Weill Cornell Medical College who led the study, is interested in figuring out how the immune system changes metabolically during cancer. A postdoctoral fellow in Cubillos-Ruiz’s lab, Sung-Min Hwang, noticed that a protein involved in cytoskeleton organization called transgelin 2 (TAGLN2) was strongly suppressed in T cells from ovarian tumors. “I had never really appreciated this [protein] factor before,” said Hwang, a coauthor on the study. 

After searching the literature, the scientists found that TAGLN2 was involved in lipid uptake in T cells. When they isolated T cells from ovarian cancer patients, they found that their lipid uptake was impaired compared to T cells from healthy controls. They also saw that the protein fatty acid binding protein 5 (FABP5), which is important for fat transport into cells, localized to the wrong spot in the T cells from ovarian cancer patients. 

To investigate the potential connection between TAGLN2 and FABP5, the team performed immunoprecipitation experiments and found that FABP5 and TAGLN2 are biological partners in crime; they’re normally bound to one another. Without TAGLN2, FABP5 could not work properly, leading to impaired lipid uptake in these tumor-adjacent T cells. 

The next piece of the mystery was what was downregulating TAGLN2 in the T cells. To do that, Cubillos-Ruiz and his team looked at the genomic regions surrounding the TAGLN2 gene in these T cells to see where transcription factor proteins were binding. They saw that there were several binding sites for transcription factors associated with endoplasmic reticulum stress — a phenomenon commonly found in cancer environments. They found that in these cancer-adjacent T cells, the transcription factor X-box binding protein 1 (XBP1) was more active, which downregulated TAGLN2 protein expression. 

This, then, was the key step that was dysregulated in T cells during ovarian cancer. The cancer environment produced intense amounts of stress, causing transcription factor XBP1 to bind and downregulate TAGLN2. And without TAGLN2, FABP5 could not work properly. All of this led to impaired fatty acid uptake in these T cells and ultimately an impaired immune response. 

With a clear mechanism in hand, Cubillos-Ruiz and Hwang decided to leverage chimeric antigen receptor (CAR) T cells to build a potential new ovarian cancer therapy. They started by using a special type of CAR T called a chimeric endocrine receptor (CER) T cell, which is engineered to target cancer cells that carry endocrine hormone receptors specific to ovarian tumors (2). The scientists then designed the CER T cell to overexpress TAGLN2. They found the CER T cells significantly slowed tumor growth in mice with ovarian cancers. 

“The mechanistic insight from this paper is fantastic,” said O’Connor, who was unaffiliated with the study. He noted that ovarian cancers are often next to the stomach omentum, essentially a fatty curtain with ample amounts of lipids. This paper, he said, helped explain why cancer cells can use these nearby lipids to power their growth while T cells cannot. 

Hwang is curious to see what other biological processes, perhaps in metabolism, are dysregulated in immune cells and can be exploited to design more effective therapeutics. “What is the next mechanism that we can use to boost these CAR T therapies in the future?” he mused. 

All in all, Cubillos-Ruiz and Hwang hope to use this discovery to design better immunotherapies for ovarian cancer. “Hopefully we can exploit this knowledge for other types of cellular immunotherapies, especially in solid tumor types like breast or pancreatic cancer,” said Cubillos-Ruiz. 

References

  1. Hwang, S.-M. et al. Transgelin 2 guards T cell lipid metabolism and antitumour function. Nature  635, 1010–1018 (2024). 
  2. Perales-Puchalt, A. et al. Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target. Clin Cancer Res 23, 441–453 (2017).

About the Author

  • Maggie Chen Headshot
    Maggie is a Harvard graduate and science journalist who enjoys watching heart cells beat under a microscope and writing about health, biotech, and history.

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