Immune Inhibitory Mechanisms and New Insights into Ovarian Cancer Treatment

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 9148

Special Issue Editors


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Guest Editor
Independent Laboratory of Cancer Diagnostics and Immunology, Department of Oncological Gynaecology and Gynaecology, Faculty of Medicine, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland
Interests: ovarian cancer microenvironment; immune checkpoints; tumor-infiltrating immune cells; immunotherapy

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Guest Editor
Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland
Interests: cancer immunology; macrophages; myeloid-derived suppressor cells; γδ T cells; flow cytometry
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Special Issue Information

Dear Colleagues,

Ovarian cancer (OC) is one of the most lethal gynecological malignancies. Its high mortality rate is a result of the lack of screening methods and specific symptoms of the disease, related to the extreme heterogeneity of OC, including genomic, transcriptomic, proteomic, and, the least understood of all, immunologic aspects. Currently, we acknowledge that the immune system plays a dual role in OC. It can not only suppress tumor growth by eliminating cancer cells or inhibiting their outgrowth, but can also promote tumor progression. OC development and progression are highly dependent on the specific tumor microenvironment (TME). Understanding how the composition of the TME changes during OC development and progression is a prerequisite for projecting therapeutic strategies to tackle the tumor at a specific evolutionary stage, which is important for the selection of the most suitable therapy.

The latest advances in the field of tumor immunology and immunotherapy emphasize that ovarian cancer cells can evade the host's immune response and stimulate tumor development by deactivation or death of crucial immune system effector cells, i.e., T cells and NK cells. One of the negative regulators of activated T cells are immune checkpoint inhibitors (ICPs), e.g., programmed cell-death receptor 1 (PD-1) and its ligands (PD-L1, PD-L2), T-cell immunoglobulin, and ITIM domain (TIGIT) and T-cell immunoglobulin-3 (TIM-3) and its ligand galectin 9 (Gal-9) axis. The co-expression status of ICPs on T cells in the OC TME is pivotal to understanding the complex immune-inhibitory mechanism. The synergistic model of action of these immune factors may be a promising target in ovarian cancer treatment.

This Special Issue of Biomedicines will present research articles and reviews exploring mechanisms of ovarian cancer escaping from immune surveillance, tissue invasion, and metastasis, and current as well as novel immune-modulating/inhibiting strategies in the treatment of OC. All scientists working in these fields are cordially invited to submit their manuscripts.

Prof. Dr. Iwona Wertel
Dr. Agnieszka A. Bojarska-Junak
Guest Editors

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Keywords

  • ovarian cancer microenvironment
  • tumor-infiltrating immune cells
  • inflammation and ovarian cancer
  • dendritic cell subsets
  • monocytes/macrophages
  • myeloid-derived suppressor cells
  • γδ T cells
  • microRNA
  • immune checkpoints
  • resistance to therapy
  • immunotherapy of ovarian cancer
  • clinical trials in ovarian cancer

Published Papers (4 papers)

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Research

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13 pages, 2161 KiB  
Article
Expression of CISH, an Inhibitor of NK Cell Function, Increases in Association with Ovarian Cancer Development and Progression
by Jasmin C. Acosta, Janice M. Bahr, Sanjib Basu, James T. O’Donnell and Animesh Barua
Biomedicines 2023, 11(2), 299; https://doi.org/10.3390/biomedicines11020299 - 21 Jan 2023
Viewed by 1809
Abstract
Epithelial ovarian cancer (OVCA), a fatal malignancy of women, disseminates locally. Although NK cells mount immune responses against OVCA, tumors inhibit NK cells, and the mechanism is not well understood. Cytokines stimulate NK cells; however, chronic stimulation exhausts them and induces expression of [...] Read more.
Epithelial ovarian cancer (OVCA), a fatal malignancy of women, disseminates locally. Although NK cells mount immune responses against OVCA, tumors inhibit NK cells, and the mechanism is not well understood. Cytokines stimulate NK cells; however, chronic stimulation exhausts them and induces expression of cytokine-inducible SH2-containing protein (CISH). Tumors produce anti-inflammatory cytokine interleukin (IL)-10 which may induce NK cell exhaustion. The goal of this study was to examine if CISH expression in NK cells increases during OVCA development and to determine the mechanism(s) of OVCA-induced CISH expression in NK cells. Normal ovaries (n = 7) were used for CISH, IL-10 and GRP78 expression. In tumor ovaries, CISH was examined in early and late stages (n = 14 each, all subtypes) while IL-10 and GRP78 expression were examined in early and late stage HGSC (n = 5 each). Compared to normal, the population of CISH-expressing NK cells increased and the intensity of IL-10 and GRP78 expression was significantly higher in OVCA (p < 0.05). CISH expression was positively correlated with IL-10 expression (r = 0.52, r = 0.65, p < 0.05 at early and late stages, respectively) while IL-10 expression was positively correlated with GRP78 expression (r = 0.43, r = 0.52, p < 0.05, respectively). These results suggest that OVCA development and progression are associated with increased CISH expression by NK cells which is correlated with tumor-induced persistent cellular stress. Full article
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9 pages, 248 KiB  
Article
Endometrial Heparin-Binding Epidermal Growth Factor Gene Expression and Hormone Level Changes in Implantation Window of Obese Women with Polycystic Ovarian Syndrome
by Zulazmi Sutaji, Muhammad Azrai Abu, Nurainie Sayutti, Marjanu Hikmah Elias, Mohd Faizal Ahmad, Abdul Ghani Nur Azurah, Kah Teik Chew, Abdul Kadir Abdul Karim, Nor Haslinda Abd Aziz, Mohd Helmy Mokhtar, Reena Rahayu Md Zin and Zeti Azura Mohamed Hussein
Biomedicines 2023, 11(2), 276; https://doi.org/10.3390/biomedicines11020276 - 19 Jan 2023
Cited by 2 | Viewed by 1405
Abstract
Introduction: Polycystic ovarian syndrome (PCOS) is a common endocrine disorder amongst reproductive-age women, and 61% to 76% of women with PCOS are obese. Obese women with PCOS are usually burdened with infertility problems due to implantation failure. Thus, progesterone treatment is usually used [...] Read more.
Introduction: Polycystic ovarian syndrome (PCOS) is a common endocrine disorder amongst reproductive-age women, and 61% to 76% of women with PCOS are obese. Obese women with PCOS are usually burdened with infertility problems due to implantation failure. Thus, progesterone treatment is usually used to improve implantation rates. Although Hb-EGF expression is actively involved in endometrial receptivity and implantation, the data on heparin-binding epidermal growth factor (Hb-EGF) expression following progesterone therapy in obese women with PCOS are still lacking. Objective: To investigate the changes in serum follicle-stimulating hormone (FSH), luteinising hormone (LH), dehydroepiandrosterone sulphate (DHEA), progesterone and oestradiol levels and Hb-EGF expression in obese women with PCOS during the implantation window following progesterone therapy. Method: A total of 40 participants aged 18–40 years old were recruited following the provision of written consent. The participants were divided into the obese PCOS, normal-weight PCOS, obese fertile and normal-weight fertile groups. First blood collection was done before ovulation. Then, daily oral micronised progesterone (Utrogestan 200 mg) was given to the PCOS group for 10 days. The treatment was followed by a second blood collection and endometrial tissue sampling by using a Pipelle de Cornier catheter. In the fertile group, ovulation was confirmed by using ultrasound, and a second blood sample was collected on days 7 to 9 postovulation. The serum levels of FSH, LH, DHEA, progesterone and oestradiol were measured in all participants. Wilcoxon signed-rank test was used to compare FSH, LH, DHEA, progesterone and oestradiol levels during pre- and postovulation. Mann–Whitney test was performed to compare FSH, LH, DHEA, progesterone and oestradiol levels between two groups: (1) the PCOS group and the fertile group, (2) the obese PCOS group and the non-obese PCOS group and (3) the obese group and the non-obese fertile group. Result: Serum FSH levels were lower in obese women in their follicular phase than in women with normal weight regardless of their PCOS status, whereas serum LH/FSH ratios and DHEA levels were higher in women with PCOS than in women without PCOS. However, endometrial Hb-EGF expression was lower in the obese PCOS group than in the normal-weight PCOS group. Conclusions: Different patterns of hormonal levels and Hb-EGF expression levels were seen between the studied groups. However, further in vitro and in vivo studies are needed to investigate the mechanism underlying the changes in FSH, LH/FSH ratio, DHEA and Hb-EGF expression in PCOS after progesterone treatment. Full article
13 pages, 3441 KiB  
Article
Combined Usage of MDK Inhibitor Augments Interferon-γ Anti-Tumor Activity in the SKOV3 Human Ovarian Cancer Cell Line
by Qun Liu, Jingyu Tan, Zhenguo Zhao, Ruijun Li, Luyu Zheng, Xiangyu Chen, Lina Li, Xichen Dong, Tao Wen and Jian Liu
Biomedicines 2023, 11(1), 8; https://doi.org/10.3390/biomedicines11010008 - 21 Dec 2022
Cited by 3 | Viewed by 1985
Abstract
Ovarian cancer (OC) is a particularly lethal disease due to intratumoral heterogeneity, resistance to traditional chemotherapy, and poor response to targeted therapy and immunotherapy. Interferon-γ (IFN-γ) is an attractive therapeutic cytokine, with positive responses achieved in multiple OC clinical trials. However, clinical application [...] Read more.
Ovarian cancer (OC) is a particularly lethal disease due to intratumoral heterogeneity, resistance to traditional chemotherapy, and poor response to targeted therapy and immunotherapy. Interferon-γ (IFN-γ) is an attractive therapeutic cytokine, with positive responses achieved in multiple OC clinical trials. However, clinical application of IFN-γ in OC is still hindered, due to the severe toxicity when used at higher levels, as well as the considerable pro-metastatic adverse effect when used at lower levels. Thus, an effective combined intervention is needed to enhance the anti-tumor efficacy of IFN-γ and to suppress the IFN-γ-induced metastasis. Here, we uncovered that OC cells develop an adaptive strategy by upregulating midkine (MDK) to counteract the IFN-γ-induced anti-tumor activity and to fuel IFN-γ-induced metastasis. We showed that MDK is a critical downstream target of IFN-γ in OC, and that this regulation acts in a dose-dependent manner and is mediated by STAT1. Gain-of-function studies showed that MDK overexpression promotes cell proliferation and metastasis in OC, indicating that IFN-γ-activated MDK may antagonize IFN-γ in inhibiting OC proliferation but synergize IFN-γ in promoting OC metastasis. Subsequently, we assessed the influence of MDK inhibition on IFN-γ-induced anti-proliferation and pro-metastasis effects using an MDK inhibitor (iMDK), and we found that MDK inhibition robustly enhanced IFN-γ-induced growth inhibition (all CIs < 0.1) and reversed IFN-γ-driven epithelial-to-mesenchymal transition (EMT) and metastasis in OC in vitro. Collectively, these data identify an IFN-γ responsive protein, MDK, in counteracting anti-proliferation while endowing the pro-metastatic role of IFN-γ in cancer treatment, and we therefore propose the combined utilization of the MDK inhibitor in IFN-γ-based therapies in future OC treatment. Full article
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Review

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17 pages, 950 KiB  
Review
The Role of TIM-3 and LAG-3 in the Microenvironment and Immunotherapy of Ovarian Cancer
by Mateusz Kozłowski, Dominika Borzyszkowska and Aneta Cymbaluk-Płoska
Biomedicines 2022, 10(11), 2826; https://doi.org/10.3390/biomedicines10112826 - 5 Nov 2022
Cited by 14 | Viewed by 3272
Abstract
Ovarian cancer has the highest mortality rate among gynecologic malignancies. The main treatment options are surgical removal of the tumor and chemotherapy. Cancer treatment has been revolutionized by immunotherapy, which has developed explosively over the past two decades. Clinical anticancer strategies used in [...] Read more.
Ovarian cancer has the highest mortality rate among gynecologic malignancies. The main treatment options are surgical removal of the tumor and chemotherapy. Cancer treatment has been revolutionized by immunotherapy, which has developed explosively over the past two decades. Clinical anticancer strategies used in immunotherapy include therapies based on the inhibition of PD-1, PD-L1 or CTLA-4. Despite encouraging results, a large proportion of cancer patients are resistant to these therapies or eventually develop resistance. It is important to perform research that will focus on immunotherapy based on other immune checkpoint inhibitors. The aim of the review was to analyze studies considering the expression of TIM-3 and LAG-3 in the ovarian cancer microenvironment and considering immunotherapy for ovarian cancer that includes antibodies directed against TIM-3 and LAG-3. As the data showed, the expression of the described immune checkpoints was shown in different ways. Higher TIM-3 expression was associated with a more advanced tumor stage. Both TIM-3 and LAG-3 were co-expressed with PD-1 in a large proportion of studies. The effect of LAG-3 expression on progression-free survival and/or overall survival is inconclusive and certainly requires further study. Co-expression of immune checkpoints prompts combination therapies using anti-LAG-3 or anti-TIM-3. Research on immune checkpoints, especially TIM-3 and LAG-3, should be further developed. Full article
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