Ovarian cancer ranks as the fifth leading cause of cancer-related mortality in women and is the most lethal of all gynaecologic malignancies. Despite improvements in diagnostic and therapeutic modalities, the 5-year survival rate for advanced-stage ovarian cancer remains dismally low. The lifetime risk for women developing ovarian cancer is approximately 1 in 78.
The high mortality rate is largely attributable to late-stage diagnosis and limited efficacy of current treatment strategies, which have remained largely unchanged for decades, relying heavily on cytoreductive surgery and platinum-based chemotherapy. Although research in targeted therapy and immunotherapy has advanced, clinical outcomes have not significantly improved. This underscores the urgent need for innovative therapeutic approaches, particularly those involving immune-based and stem cell-derived strategies.
Emerging Role of Immunotherapy
Immunotherapy, which harnesses the patient’s immune system to recognize and destroy cancer cells, has revolutionized the treatment landscape for several malignancies. However, its success in ovarian cancer has been limited, likely due to the immunosuppressive tumour microenvironment (TME). Active investigations are exploring immune checkpoint inhibitors (ICIs), cancer vaccines, and adoptive cell therapy (ACT) to overcome this resistance.
Neutrophils and Natural Killer (NK) Cells in the Tumour Microenvironment
Neutrophils and NK cells, integral components of innate immunity, play a dual role in cancer. Neutrophils constitute 50–70% of circulating leukocytes and are capable of adopting pro-tumour (N2) or anti-tumour (N1) phenotypes, modulated by TME signals. N1 neutrophils express TNF-α, CCL3, and ICAM1, exerting cytotoxic effects, while N2 neutrophils promote tumorigenesis through secretion of VEGF, MMP9, and immunosuppressive cytokines.
Similarly, NK cells are subdivided into cytotoxic CD56dimCD16+ cells and cytokine-producing CD56brightCD16− cells. Their cytotoxic activity is regulated by the balance of activating and inhibitory receptor signaling, particularly in response to downregulated MHC I expression on tumour cells. Decidual-like NK cells within TME exhibit pro-angiogenic properties, complicating their role in tumour suppression.
Neutrophil – NK Cell Crosstalk
The interplay between neutrophils and NK cells further complicates immunotherapy. Neutrophils can suppress NK function by reducing CCR1 expression or modulating NKp46 via reactive oxygen species (ROS), elastase, and cathepsin G. Conversely, NK-derived IFNγ can reverse the pro-angiogenic phenotype of tumour-associated neutrophils (TANs), highlighting a potential avenue for therapeutic modulation (Palano et al., 2021).
Adoptive Cell Therapy Using UCB – Derived Immune Cells
Cord blood-derived neutrophils and NK cells represent promising tools for ACT. For instance, lipopolysaccharide (LPS) and IL-8 activated neutrophils from umbilical cord blood (UCB) significantly inhibited ovarian cancer progression in vitro and in vivo (Liu et al., 2020). UCB-derived NK cells expanded with SR1, IL-15, and IL-12 demonstrated potent intraperitoneal cytotoxicity against ovarian cancer spheroids in xenograft models (Hoogstad-van Evert et al., 2017).
Mesenchymal Stem Cells and Their Secretome
Mesenchymal stem cells (MSCs), owing to their immunomodulatory properties and tumour-homing capabilities, are being investigated for both anti-cancer therapy and preservation of fertility postchemotherapy. The therapeutic effects of MSCs are largely mediated through paracrine signaling via their secretome, which includes cytokines, growth factors, lipids, mRNAs, and miRNAs.
Conditioned medium (CM) derived from MSCs offers advantages such as easier storage and reduced immunogenicity, without the risk of malignant transformation. CM from human amniotic epithelial cells and hUCMSCs has been shown to reduce ovarian damage, restore follicular reserve, and protect against cisplatin-induced toxicity (Shareghi-Oskoue et al., 2021; ArefNezhad et al., 2023).
Clinical Implications and Future Directions
Stem cell-based therapies, including the use of hUCMSC-secreted IL-21 or preconditioned CM, have shown efficacy in animal models of ovarian cancer and chemotherapy-induced ovarian insufficiency. Furthermore, MSC-derived exosomes loaded with anti-cancer agents are under investigation as smart drug delivery platforms.
Despite these advancements, challenges remain in optimizing the source, scale-up, and functional stability of MSC-derived therapies. Clinical trials evaluating MSC and CM-based interventions, in conjunction with immunotherapies such as NK cell infusions or ICIs, could pave the way for breakthrough treatments. Since 2023, significant advancements have been made in stem cell research related to ovarian cancer, focusing on understanding cancer stem cells (CSCs), developing targeted therapies, and improving early detection methods.
Understanding Cancer Stem Cells in Ovarian Cancer
Cancer stem cells are a subpopulation of tumour cells that contribute to tumour growth, metastasis, and resistance to chemotherapy. Recent studies have emphasized the importance of targeting these cells to improve treatment outcomes:
- Signaling Pathways and Markers: Research has identified key signaling pathways, such as JAK/STAT and Hedgehog, that regulate ovarian cancer stem cell properties. Understanding these pathways can aid in developing targeted therapies .
- Therapeutic Targets: A study highlighted the role of the CD55 protein in promoting chemoresistance and aggressive cancer stem cell growth in ovarian cancer. Targeting CD55 may offer a new approach to treat chemotherapy-resistant ovarian cancer.
Innovative Stem Cell-Based Therapies
Emerging therapies are leveraging stem cells to deliver treatments directly to ovarian tumours:
- Neural Stem Cells and Oncolytic Viruses: Researchers are exploring the use of neural stem cells to deliver oncolytic viruses directly to abdominal ovarian tumour sites. This approach aims to infect and kill tumour cells, including those resistant to chemotherapy, and stimulate the patient’s immune system to fight the cancer .
- CAR-NK Cell Therapy: Advancements in immunotherapy include engineering natural killer (NK) cells with chimeric antigen receptors (CARs) to target ovarian cancer cells more effectively. These CARNK cells are designed to be more aggressive in killing tumour cells and are being considered for direct delivery into the pelvic cavity where ovarian cancer is located.
Early Detection and Prevention Strategies
Understanding the origins of ovarian cancer is crucial for early detection:
- High-Risk Mesenchymal Stem Cells (MSCs): A recent study identified a subgroup of mesenchymal stem cells that may play a critical role in the formation of precancerous lesions in the fallopian tubes, which can lead to high-grade serous ovarian cancer. These findings could lead to new methods for early detection or prevention of the disease.
These developments represent promising steps toward more effective and personalized treatments for ovarian cancer, particularly in overcoming chemoresistance and improving early detection.
Conclusion
Ovarian cancer, though resistant to current immunotherapeutic modalities, displays immunogenic features that can be exploited using neutrophil and NK cell-based ACT, as well as MSC-derived regenerative therapies. Harnessing the immune system and stem cell biology in a synergistic manner could transform the therapeutic landscape for this deadly disease.
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