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Elevated Galectin-3 levels in the tumor microenvironment of ovarian cancer – implication of ROS mediated suppression of NK cell antitumor response via tumor-associated neutrophils

Karlsson, Veronika ; Stål, Ebba ; Stoopendahl, Emma ; Ivarsson, Anton ; Leffler, Hakon LU ; Lycke, Maria ; Sundqvist, Martina ; Sundfeldt, Karin ; Christenson, Karin and Bernson, Elin (2024) In Frontiers in Immunology 15.
Abstract

Introduction: Ovarian cancer is a lethal disease with low survival rates for women diagnosed in advanced stages. Current cancer immunotherapies are not efficient in ovarian cancer, and there is therefore a significant need for novel treatment options. The β-galactoside-binding lectin, Galectin-3, is involved in different immune processes and has been associated with poor outcome in various cancer diagnoses. Here, we investigated how Galectin-3 affects the interaction between natural killer (NK) cells and neutrophils in the tumor microenvironment of ovarian cancer. Method: Ascites from the metastatic tumor microenvironment and cyst fluid from the primary tumor site were collected from patients with high-grade serous carcinoma (HGSC)... (More)

Introduction: Ovarian cancer is a lethal disease with low survival rates for women diagnosed in advanced stages. Current cancer immunotherapies are not efficient in ovarian cancer, and there is therefore a significant need for novel treatment options. The β-galactoside-binding lectin, Galectin-3, is involved in different immune processes and has been associated with poor outcome in various cancer diagnoses. Here, we investigated how Galectin-3 affects the interaction between natural killer (NK) cells and neutrophils in the tumor microenvironment of ovarian cancer. Method: Ascites from the metastatic tumor microenvironment and cyst fluid from the primary tumor site were collected from patients with high-grade serous carcinoma (HGSC) together with peripheral blood samples. Galectin-3 concentration was measured in ascites, cyst fluid and serum or plasma. Neutrophils isolated from HGSC ascites and autologous blood were analyzed to evaluate priming status and production of reactive oxygen species. In vitro co-culture assays with NK cells, neutrophils and K562 target cells (cancer cell line) were conducted to evaluate NK cell viability, degranulation and cytotoxicity. Results: High levels of Galectin-3 were observed in cyst fluid and ascites from patients with HGSC. Neutrophils present in HGSC ascites showed signs of priming; however, the priming status varied greatly among the patient samples. Galectin-3 induced production of reactive oxygen species in ascites neutrophils, but only from a fraction of the patient samples, which is in line with the heterogenous priming status of the ascites neutrophils. In co-cultures with NK cells and K562 target cells, we observed that Galectin-3-induced production of reactive oxygen species in neutrophils resulted in decreased NK cell viability and lowered anti-tumor responses. Conclusion: Taken together, our results demonstrate high levels of Galectin-3 in the tumormicroenvironment of HGSC. High levels of Galectin-3 may induce production of reactiveoxygen species in ascites neutrophils in some patients. In turn, reactive oxygen species produced by neutrophils may modulate the NK cell anti-tumor immunity. Together, this study suggests further investigation to evaluate if a Galectin-3-targeting therapy may be used in ovarian cancer.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
galectin-3, neutrophils, NK cells, ovarian cancer, ROS release, tumor immunology, tumor microenvironment
in
Frontiers in Immunology
volume
15
article number
1506236
publisher
Frontiers Media S. A.
external identifiers
  • scopus:85213839048
  • pmid:39759523
ISSN
1664-3224
DOI
10.3389/fimmu.2024.1506236
language
English
LU publication?
yes
id
d072214d-3211-4abc-8b29-96cacb663f28
date added to LUP
2025-02-24 14:28:52
date last changed
2025-07-15 01:57:58
@article{d072214d-3211-4abc-8b29-96cacb663f28,
  abstract     = {{<p>Introduction: Ovarian cancer is a lethal disease with low survival rates for women diagnosed in advanced stages. Current cancer immunotherapies are not efficient in ovarian cancer, and there is therefore a significant need for novel treatment options. The β-galactoside-binding lectin, Galectin-3, is involved in different immune processes and has been associated with poor outcome in various cancer diagnoses. Here, we investigated how Galectin-3 affects the interaction between natural killer (NK) cells and neutrophils in the tumor microenvironment of ovarian cancer. Method: Ascites from the metastatic tumor microenvironment and cyst fluid from the primary tumor site were collected from patients with high-grade serous carcinoma (HGSC) together with peripheral blood samples. Galectin-3 concentration was measured in ascites, cyst fluid and serum or plasma. Neutrophils isolated from HGSC ascites and autologous blood were analyzed to evaluate priming status and production of reactive oxygen species. In vitro co-culture assays with NK cells, neutrophils and K562 target cells (cancer cell line) were conducted to evaluate NK cell viability, degranulation and cytotoxicity. Results: High levels of Galectin-3 were observed in cyst fluid and ascites from patients with HGSC. Neutrophils present in HGSC ascites showed signs of priming; however, the priming status varied greatly among the patient samples. Galectin-3 induced production of reactive oxygen species in ascites neutrophils, but only from a fraction of the patient samples, which is in line with the heterogenous priming status of the ascites neutrophils. In co-cultures with NK cells and K562 target cells, we observed that Galectin-3-induced production of reactive oxygen species in neutrophils resulted in decreased NK cell viability and lowered anti-tumor responses. Conclusion: Taken together, our results demonstrate high levels of Galectin-3 in the tumormicroenvironment of HGSC. High levels of Galectin-3 may induce production of reactiveoxygen species in ascites neutrophils in some patients. In turn, reactive oxygen species produced by neutrophils may modulate the NK cell anti-tumor immunity. Together, this study suggests further investigation to evaluate if a Galectin-3-targeting therapy may be used in ovarian cancer.</p>}},
  author       = {{Karlsson, Veronika and Stål, Ebba and Stoopendahl, Emma and Ivarsson, Anton and Leffler, Hakon and Lycke, Maria and Sundqvist, Martina and Sundfeldt, Karin and Christenson, Karin and Bernson, Elin}},
  issn         = {{1664-3224}},
  keywords     = {{galectin-3; neutrophils; NK cells; ovarian cancer; ROS release; tumor immunology; tumor microenvironment}},
  language     = {{eng}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Immunology}},
  title        = {{Elevated Galectin-3 levels in the tumor microenvironment of ovarian cancer – implication of ROS mediated suppression of NK cell antitumor response via tumor-associated neutrophils}},
  url          = {{http://dx.doi.org/10.3389/fimmu.2024.1506236}},
  doi          = {{10.3389/fimmu.2024.1506236}},
  volume       = {{15}},
  year         = {{2024}},
}