(Press-News.org) MAY 9, 2025, NEW YORK – A Ludwig Cancer Research study has identified a key mechanism by which advanced ovarian cancers suppress anti-tumor immune responses and resist immunotherapies. Led by Ludwig Princeton’s Lydia Lynch and reported in the current issue of Science Immunology, the study details how ascites fluid—produced in large quantities as ovarian cancer spreads from the ovaries into the abdomen and its organs—sabotages cytotoxic lymphocytes, a class of immune cells that kill cancer cells.
“Although ascites fluid has long been known to be immunosuppressive, it has not been clear what precisely gives it that property,” explained Lynch. “We discovered through the large-scale analysis of metabolic building blocks and byproducts in ascites that certain types of fat, or lipids, found at high levels in the fluid cripple three types of cytotoxic lymphocytes: natural killer (NK) cells, T cells and innate T cells. Our studies also identify a mechanism of lipid import employed by NK cells that drives this dysfunction, and provide evidence suggesting it might be targeted for immunotherapy against ovarian cancer.”
Owing to the vagueness of symptoms and the lack of reliable screening tests, more than 70% of women already have metastatic disease by the time they are diagnosed with high-grade serous ovarian cancer (HGSOC). This partly accounts in part for why only about 10-15% of HGSOC patients evaluated in clinical trials have responded to immune checkpoint blockade, a type of immunotherapy that stimulates a T cell assault on tumors.
NK cells also infiltrate tumors and are considered attractive candidates for cellular immunotherapies, in which immune cells taken for a patient are grown in the laboratory and reinfused for cancer therapy. Unlike T cells, which are highly specific in their targeting of malignant cells and must be carefully selected to be effective agents of therapy, NK cells are generalists when it comes to killing cancer cells. They are also less likely than T cells to cause dangerous autoimmune reactions. But NK cells tend to suffer acute metabolic dysfunction in cancer patients, which compromises their therapeutic efficacy.
In the current study, Lynch and her colleagues—including first author Karen Slattery of Trinity College Dublin, and senior author Marcia Haigis of Ludwig Harvard—first examined cytotoxic lymphocytes isolated from primary and metastatic tumors in patients and found that all subtypes were functionally crippled. Notably, all of them tended to produce very low levels of perforin and granzyme B, molecules that, respectively, poke holes in targeted cells and drive them to programmed death.
The researchers next explored the potential causes of NK cell dysfunction. A large-scale analysis of metabolic byproducts and building blocks in ascites obtained from untreated HGSOC patients revealed that the fluid is rich in nutrients, like amino acids and glucose— which are required for lymphocyte function—as well as fats.
After examining and ruling out other potential causes of NK cell dysfunction in ascites, the researchers examined whether metabolic factors might explain the phenomenon. Their experiments revealed that fats play a central role in the observed immune cell dysfunction.
NK cells, they found, are so overwhelmed by the influx of certain types of lipids in ascites—especially a metabolite known as phosphatidylcholine (36:1)—that they become incapable of handling, storing and processing fats. This dysfunction, in turn, undermines their ability to take up and use amino acids and glucose. Starved of these critical nutrients, NK cells switch off their production of stimulatory immune factors like IFNγ and TNFα and shut down their cell-killing machinery.
Lynch and her colleagues report that these dysfunctions could be reversed by depleting lipids from the ascites. Doing so restored the ability of NK cells to import glucose, express granzyme B, produce IFNγ and TNFα and kill cancer cells. Other types of cytotoxic lymphocytes also produced more granzyme B when lipids were depleted from ascites, suggesting lipids may be more generally responsible for the immunosuppressive properties of ascites.
The researchers also identified a transporter of lipids, SCARB1, that is expressed at high levels on the surface of NK cells exposed to ascites fluid and plays a key role in their dysfunction. They show in cell culture experiments that blocking lipid import by SCARB1 restores the uptake of vital nutrients and boosts the cytotoxic function of NK cells even when they’re bathed in malignant ascites.
“Understanding how ascites affects the immune response to ovarian cancer should be of great value to the field,” said Lynch. “We can now test various strategies for targeting lipid import by immune cells to see if any of them might restore anti-tumor immunity or improve the efficacy of immunotherapy in ovarian cancer patients.”
This study was supported by Ludwig Institute for Cancer Research, the Ludwig Center at Harvard, the Irish Cancer Society, the U.S. National Institutes of Health, Science Foundation Ireland, the Ireland East Hospital Group, the National Maternity Hospital Foundation, the Glenn Foundation for Medical Research, the American Association for Cancer Research and The Company of Biologists.
Lydia Lynch is a full member of the Princeton Branch of the Ludwig Institute for Cancer Research and a professor in the Department of Molecular Biology at Princeton University.
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About Ludwig Cancer Research
Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 50 years. Ludwig combines basic science with the translation and clinical evaluation of its discoveries to accelerate the development of new cancer diagnostics, therapies and prevention strategies. Since 1971, Ludwig has invested nearly $3 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit www.ludwigcancerresearch.org.
For additional information please contact communications@ludwigcancerresearch.org.
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