Research, headed by teams at Trinity College Dublin and University College Dublin, has uncovered how lipid-rich fluid in the abdomen, known as ascites, plays a central role in weakening the body’s immune response in advanced ovarian cancer.
The scientists explored how ascites disrupt immune cell function, with a particular focus on natural killer (NK) cells and T cells, which are key players in the body’s ability to eliminate tumors. By analyzing the contents of ascites fluid from ovarian cancer patients, they identified a group of fat molecules called phospholipids as key drivers of this immune dysfunction, suggesting that the lipids suppress the tumor-killing properties of natural killer (NK) cells.
The findings offer new insights into immune suppression in ovarian cancer and open promising avenues for future immunotherapy strategies. “We found that these lipids interfere with NK cell metabolism and suppress their ability to kill cancer cells,” said Karen Slattery, PhD, Research Fellow at the Trinity Translational Medicine Institute. “Crucially, we also discovered that blocking the uptake of these phospholipids into NK cells using a specific receptor blocker can restore their anti-tumor activity, which offers a compelling new target for therapeutic intervention.”
Slattery is first author of the team’s published paper in Science Immunology, titled “Uptake of lipids from ascites drives NK cell metabolic dysfunction in ovarian cancer.” In their paper the team reported, “… we identify polar lipids as central mediators of lymphocyte immunosuppression in ascites …These lipids caused dysregulation of NK cell lipid metabolism homeostasis and impaired cytotoxic function.”
“High-grade serous ovarian cancer (HGSOC) is an unmet clinical need, with limited treatment options and a 5-year survival rate of just 28%,” the authors wrote. “More than 70% of patients already have metastatic disease at diagnosis.”
Many patients develop large volumes of ascites, which promotes metastasis and is associated with poor therapeutic response and survival. This ascites fluid not only supports the spread of cancer throughout the abdominal cavity but also significantly impairs the body’s immune defenses, although the underlying mechanisms remain poorly understood, the team continued. “Understanding the impact of ascites on the immune system is critical for developing effective immunotherapies for patients with metastatic ovarian cancer.”
Natural killer cells are antitumor lymphocytes that have several advantages as targets for immunotherapy, Slattery and colleagues suggested. “Unlike T cells, they are not tumor antigen specific and pose lower risks of graft versus-host disease or cytokine storms in cell therapy … Critically, NK cells defend against metastasis, and their infiltration into tumors correlates with a better prognosis in metastatic cancers.”
However, NK cells can become dysfunctional in patients with cancer, the authors commented. “Despite the potential of NK cells as prospective immunotherapy targets, a better understanding of the mechanisms driving NK cell dysfunction in cancer is needed to overcome immunosuppressive factors.”
![Human NK cells have large nuclei stained in blue and droplets of fat stores stained in red. [Dr Karen Slattery, Trinity College Dublin]](https://www.genengnews.com/wp-content/uploads/2025/05/low-res-2-300x218.jpeg "Human NK cells have large nuclei stained in blue and droplets of fat stores stained in red. [Dr Karen Slattery, Trinity College Dublin]")
Human NK cells have large nuclei stained in blue and droplets of fat stores stained in red. [Dr Karen Slattery, Trinity College Dublin]
For their newly reported study the scientists examined blood, tumor, and ascites samples from patients with advanced HGSOC. They found that immune cell function was suppressed across cancer sites within individual patients, and in particular, the ascites microenvironment inhibited NK cells’ tumor killing abilities.
The team found that removing NK cells from ascites rescued their antitumor function, while depleting lipids from ascites lifted immune suppression. “Removing lipids from ascites abrogated the suppression of the immune system by ascites,” they further reported. Their studies showed that NK cells took up large amounts of lipids from ascites, which caused a lipid overload that disrupted plasma membrane remodeling. The investigators speculated that disruptions to the plasma membrane could impair NK cells’ tumor cell targeting abilities, thus restricting their antitumor activity.
The experiments in addition demonstrated that NK cells in ascites upregulated the lipid transporter receptor SCARB1/SR-B1. Inhibiting lipid uptake through SR-B1 restored NK cells’ tumor killing abilities in vitro. “Blocking the uptake of lipids through SR-B1 restored the activation and antitumor functions of NK cell in ascites, highlighting SR-B1 as a potential NK cell immunotherapy target,” they stated.
The studies also pointed to the polar lipid PC(36:1) as a contributor to NK cell dysfunction in ovarian cancer, with data suggesting “… that uptake of PC(36:1), and likely other certain lipid species from ascites, results in perturbed plasma membrane order, which could disrupt their capacity to polarize toward target cells, resulting in reduced tumor killing.” The team concluded that, collectively, “… these data show that uptake of polar lipids such as PC(36:1) through SR-B1 restricts NK cell functions in ascites and that SR-B1 represents a potential immunotherapy target for boosting NK cell antitumor responses in advanced ovarian cancer.”
Slattery commented, “This work adds a critical piece to the puzzle of why ovarian cancer is so aggressive and has such poor outcomes. While the immune system is naturally equipped to detect and destroy cancer cells, this function is switched off in many individuals with ovarian cancer, and we now know that this is in part due to the fat-rich environment created by ascites.”
Prof. Lydia Lynch, PhD, formerly based in Trinity and now in Princeton University, is the senior author of the research article. She further commented, “This study marks a significant advancement in ovarian cancer research, identifying a new mechanism underpinning immune failure and laying the foundation for new therapies that could restore immune function in these patients. By targeting the fat-induced suppression of immune cells, future treatments could empower the body’s own immune defenses to fight back and in doing so, improve outcomes for ovarian cancer patients.”
The post Immune Response in Advanced Ovarian Cancer Weakened by Phospholipids in Ascites appeared first on GEN - Genetic Engineering and Biotechnology News.
The scientists explored how ascites disrupt immune cell function, with a particular focus on natural killer (NK) cells and T cells, which are key players in the body’s ability to eliminate tumors. By analyzing the contents of ascites fluid from ovarian cancer patients, they identified a group of fat molecules called phospholipids as key drivers of this immune dysfunction, suggesting that the lipids suppress the tumor-killing properties of natural killer (NK) cells.
The findings offer new insights into immune suppression in ovarian cancer and open promising avenues for future immunotherapy strategies. “We found that these lipids interfere with NK cell metabolism and suppress their ability to kill cancer cells,” said Karen Slattery, PhD, Research Fellow at the Trinity Translational Medicine Institute. “Crucially, we also discovered that blocking the uptake of these phospholipids into NK cells using a specific receptor blocker can restore their anti-tumor activity, which offers a compelling new target for therapeutic intervention.”
Slattery is first author of the team’s published paper in Science Immunology, titled “Uptake of lipids from ascites drives NK cell metabolic dysfunction in ovarian cancer.” In their paper the team reported, “… we identify polar lipids as central mediators of lymphocyte immunosuppression in ascites …These lipids caused dysregulation of NK cell lipid metabolism homeostasis and impaired cytotoxic function.”
“High-grade serous ovarian cancer (HGSOC) is an unmet clinical need, with limited treatment options and a 5-year survival rate of just 28%,” the authors wrote. “More than 70% of patients already have metastatic disease at diagnosis.”
Many patients develop large volumes of ascites, which promotes metastasis and is associated with poor therapeutic response and survival. This ascites fluid not only supports the spread of cancer throughout the abdominal cavity but also significantly impairs the body’s immune defenses, although the underlying mechanisms remain poorly understood, the team continued. “Understanding the impact of ascites on the immune system is critical for developing effective immunotherapies for patients with metastatic ovarian cancer.”
Natural killer cells are antitumor lymphocytes that have several advantages as targets for immunotherapy, Slattery and colleagues suggested. “Unlike T cells, they are not tumor antigen specific and pose lower risks of graft versus-host disease or cytokine storms in cell therapy … Critically, NK cells defend against metastasis, and their infiltration into tumors correlates with a better prognosis in metastatic cancers.”
However, NK cells can become dysfunctional in patients with cancer, the authors commented. “Despite the potential of NK cells as prospective immunotherapy targets, a better understanding of the mechanisms driving NK cell dysfunction in cancer is needed to overcome immunosuppressive factors.”
Human NK cells have large nuclei stained in blue and droplets of fat stores stained in red. [Dr Karen Slattery, Trinity College Dublin]
For their newly reported study the scientists examined blood, tumor, and ascites samples from patients with advanced HGSOC. They found that immune cell function was suppressed across cancer sites within individual patients, and in particular, the ascites microenvironment inhibited NK cells’ tumor killing abilities.
The team found that removing NK cells from ascites rescued their antitumor function, while depleting lipids from ascites lifted immune suppression. “Removing lipids from ascites abrogated the suppression of the immune system by ascites,” they further reported. Their studies showed that NK cells took up large amounts of lipids from ascites, which caused a lipid overload that disrupted plasma membrane remodeling. The investigators speculated that disruptions to the plasma membrane could impair NK cells’ tumor cell targeting abilities, thus restricting their antitumor activity.
The experiments in addition demonstrated that NK cells in ascites upregulated the lipid transporter receptor SCARB1/SR-B1. Inhibiting lipid uptake through SR-B1 restored NK cells’ tumor killing abilities in vitro. “Blocking the uptake of lipids through SR-B1 restored the activation and antitumor functions of NK cell in ascites, highlighting SR-B1 as a potential NK cell immunotherapy target,” they stated.
The studies also pointed to the polar lipid PC(36:1) as a contributor to NK cell dysfunction in ovarian cancer, with data suggesting “… that uptake of PC(36:1), and likely other certain lipid species from ascites, results in perturbed plasma membrane order, which could disrupt their capacity to polarize toward target cells, resulting in reduced tumor killing.” The team concluded that, collectively, “… these data show that uptake of polar lipids such as PC(36:1) through SR-B1 restricts NK cell functions in ascites and that SR-B1 represents a potential immunotherapy target for boosting NK cell antitumor responses in advanced ovarian cancer.”
Slattery commented, “This work adds a critical piece to the puzzle of why ovarian cancer is so aggressive and has such poor outcomes. While the immune system is naturally equipped to detect and destroy cancer cells, this function is switched off in many individuals with ovarian cancer, and we now know that this is in part due to the fat-rich environment created by ascites.”
Prof. Lydia Lynch, PhD, formerly based in Trinity and now in Princeton University, is the senior author of the research article. She further commented, “This study marks a significant advancement in ovarian cancer research, identifying a new mechanism underpinning immune failure and laying the foundation for new therapies that could restore immune function in these patients. By targeting the fat-induced suppression of immune cells, future treatments could empower the body’s own immune defenses to fight back and in doing so, improve outcomes for ovarian cancer patients.”
The post Immune Response in Advanced Ovarian Cancer Weakened by Phospholipids in Ascites appeared first on GEN - Genetic Engineering and Biotechnology News.