The Inhibition of Platelets Restore Anti-Tumor Immune Response to Ovarian Cancer and Its Therapeutic Implication

Abstract The interactions between platelets and cancer cells activate platelets and enhance tumor growth. The ability of a cancer cell line to activate platelets in vitro, tumor cell-induced platelet aggregation (TCIPA), predicts the in vivo aggressiveness of that particular cancer cell line. We have found that platelets extravasate into tumor microenvironment. We also have shown that ovarian cancer cells secret ADP that activate platelets by binding to P2Y12 (an ADP receptor on platelets). In turn, activated platelets enhance proliferation of ovarian cancer cells and tumor growth. Activated platelets release TGFβ to the tumor microenvironment (TME) that enhances cancer cell proliferation in a TGFβ dose-dependent manner. Platelet TGFβ also functions as an immune modulator by enhancing differentiation of T cells toward T-reg. Platelets not only increase cancer cell proliferation but also alter the immune response to cancer by suppressing the function of tumor-infiltrating T cells. The presence of tumor-infiltrating lymphocytes (TIL) is associated with a significant improvement in the progression-free survival (PFS) and the overall survival (OS) of patients with ovarian cancer. In the current study, we investigated the effect of platelet inhibition on promoting the immune response to tumors and the therapeutic benefit of combining anti-platelet reagents with checkpoint inhibitors (CPIs) in murine models of ovarian cancer. We have shown before, P2Y12 deficient (P2Y12-/-) and platelet specific TGFβ knockout (TGFβfl/fl;PF4-cre) mice developed smaller tumors compared to control tumor-bearing mice in a murine ovarian cancer model. To determine the effect of anti-platelet reagent in platelet extravasation into the TME, we counted the number of platelets in the TME in four groups of tumor-bearing mice: control, aspirin-treated (ASA), platelet infused (Plt) and aspirin-treated + platelet-infused (Asp Plt) mice. Platelet extravasation increased after platelet infusion and reduced after aspirin treatment. The groups with a higher number of extravasated platelets developed larger tumors compared to those with less extravasated platelets. We investigated the role of platelet in regulation of immune response to tumor using mice with platelet specific defects in murine models of ovarian cancer. We immune profiled tumors induced in mice with platelet-specific TGFβ deficiency, P2Y12 deficient mice, and aspirin or Ticagrelor-treated mice. Overall platelet functional defects was associated with an increase in the number of T cells, DC, MØ and NK and a decrease in the number of MDSCs in tumors.. We investigated the effect of immune check point inhibitors (CPI) on growth of murine ovarian cancer. We administrated 200µg of combination of CPIs (anti-CTLA4/ anti-PD-L1) into tumor-bearing mice. Combined CPI therapy had a minimal effect on the tumor burden (control=0.53± 0.082g vs. CPIs=0.33± 0.04g, p=0.15). Although CPI-treatment increased the number of CD8 cells inside tumors, it also increased the expression of VISTA (a negative) with an overall non-significant effect on the tumor growth. To investigate the effect of platelet inhibition on expression of checkpoint regulatory proteins in the TME, the expression of VISTA was examined in the tumors resected from TGFβfl/fl; PF4-cre tumor-bearing mice by quantitative RT-PCR (qRT-PCR), and was compared to that in tumors resected from WT tumor bearing mice. Tumors from TGFβfl/fl; PF4-cre mice expressed less VISTA mRNA (control= 1 vs. TGFβfl/fl; PF4-cre= 0.04 ± 0.01, p < 0.0001). Interestingly, P2Y12 deficiency and antiplatelet reagents (ticagrelor and aspirin) also reduced expression of VISTA in tumors. This is the first evidence for the effect of platelet inhibition on the expression of a checkpoint regulator in tumors. We hypothesize that platelet inhibition enhances anti-tumor immune response and can be used as an adjuvant to checkpoint inhibitors in immunotherapies for ovarian cancer. Disclosures No relevant conflicts of interest to declare.

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A Combination of Glutaminase Inhibitor 968 and PD-L1 Blockade Boosts the Immune Response against Ovarian Cancer

Biomolecules ◽

10.3390/biom11121749 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1749

Author(s):

Jing-Jing Wang ◽

Michelle Kwan-Yee Siu ◽

Yu-Xin Jiang ◽

Thomas Ho-Yin Leung ◽

David Wai Chan ◽

...

Keyword(s):

Ovarian Cancer ◽

Immune Response ◽

T Cells ◽

Cancer Cells ◽

Cd8 T Cells ◽

Granzyme B ◽

Combined Treatment ◽

In Vivo Studies ◽

Immune Checkpoints ◽

Ovarian Cancer Cells

Programmed cell death 1 ligand (PD-L1) blockade has been used therapeutically in the treatment of ovarian cancer, and potential combination treatment approaches are under investigation to improve the treatment response rate. The increased dependence on glutamine is widely observed in various type of tumors, including ovarian cancer. Kidney-type glutaminase (GLS), as one of the isotypes of glutaminase, is found to promote tumorigenesis. Here, we have demonstrated that the combined treatment with GLS inhibitor 968 and PD-L1 blockade enhances the immune response against ovarian cancer. Survival analysis using the Kaplan–Meier plotter dataset from ovarian cancer patients revealed that the expression level of GLS predicts poor survival and correlates with the immunosuppressive microenvironment of ovarian cancer. 968 inhibits the proliferation of ovarian cancer cells and enhances granzyme B secretion by CD8+ T cells as detected by XTT assay and flow cytometry, respectively. Furthermore, 968 enhances the apoptosis-inducing ability of CD8+ T cells toward cancer cells and improves the treatment effect of anti-PD-L1 in treating ovarian cancer as assessed by Annexin V apoptosis assay. In vivo studies demonstrated the prolonged overall survival upon combined treatment of 968 with anti-PD-L1 accompanied by increased granzyme B secretion by CD4+ and CD8+ T cells isolated from ovarian tumor xenografts. Additionally, 968 increases the infiltration of CD3+ T cells into tumors, possibly through enhancing the secretion of CXCL10 and CXCL11 by tumor cells. In conclusion, our findings provide a novel insight into ovarian cancer cells influence the immune system in the tumor microenvironment and highlight the potential clinical implication of combination of immune checkpoints with GLS inhibitor 968 in treating ovarian cancer.

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Platelets Promote Activation of the Complement System in Ovarian Cancer

Blood ◽

10.1182/blood-2018-99-116752 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4970-4970

Author(s):

Omayra Gonzalez Pagan ◽

Min Soon Cho ◽

Vahid Afshar-Kharghan

Keyword(s):

Ovarian Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Complement System ◽

Complement Activation ◽

Platelet Inhibition ◽

Ovarian Cancer Cells ◽

Murine Models ◽

Mesenchymal Transition ◽

The Complement System

Abstract Platelets promote metastasis and growth of ovarian cancer. We have shown that platelets extravasate into the tumor microenvironment (TME) and increase proliferation and epithelial-mesenchymal transition (EMT) in ovarian cancer cells. We have also shown that activation of the complement system in TME of ovarian cancer enhances tumor growth. Ovarian cancer cells secrete complement proteins that upon activation in the TME increase proliferation of cancer cells and promote EMT via an autocrine pathway. The activators of the complement system in the TME have not been identified. We have demonstrated that upon activation platelets activate the complement system on their surface. In the current study, we examined whether extravasated platelets inside tumors contribute to the complement activation in the TME. 1) We examined the effect of antiplatelet reagents on platelet extravasation into TME, using murine models of ovarian cancer. Tumors induced by injection of ovarian cancer cells into the peritoneum of Nu/Nu mice were resected after 6-8 weeks and the number of extravasated platelets was determined by immunostaining tumor sections and counting the number CD42 (GPIb) positive cells that were outside the blood vessels (CD31 positive). We found that platelet extravasation is an active process and platelet inhibition by aspirin or ticagrelor reduces the number of extravasated platelets. Furthermore, P2Y12 deficient platelets extravasate less than normal platelets. In all of these experiments, the number of extravasated red blood cells were significantly less than extravasated platelets and was not affected by the inhibition of platelets. 2) We examined the effect of platelet inhibition on the activation of the complement system in the TME. We immunostained resected tumors from aspirin- or ticagrelor-treated tumor-bearingmice and from P2Y12-deficient tumor-bearingmice for the endproductof complement activation (C5b-9 or membrane attack complex). Inhibition of platelet function by aspirin or ticagrelor,or the presence of hypoactive platelets in P2Y12 deficient mice reduced the amount of C5b-9 deposited in the tumors induced in murine models of ovarian cancer. Our result showed that complement activation in the TME is at least partially dependent onextravasated platelets. We propose that platelets in addition to directly increasing proliferation of ovarian cancer cells, also enhance tumor growth by activating the complement system in the vicinity of cancer cells. Our study links platelets, complement activation, and ovarian cancer growth; and raises the possibility of using antiplatelet reagents and complement inhibitors as novel synergisticanti-tumor reagents in ovarian cancer. Disclosures No relevant conflicts of interest to declare.

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Niraparib exhibits a synergistic anti-tumor effect with PD-L1 blockade by inducing an immune response in ovarian cancer

Journal of Translational Medicine ◽

10.1186/s12967-021-03073-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Jinyu Meng ◽

Jin Peng ◽

Jie Feng ◽

Jochen Maurer ◽

Xiao Li ◽

...

Keyword(s):

Ovarian Cancer ◽

Flow Cytometry ◽

Immune Response ◽

T Cells ◽

Cancer Cells ◽

Parp Inhibitors ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Sting Pathway

Abstract Background Immune checkpoint blockades (ICBs) therapy showed limited efficacy in ovarian cancer management. Increasing evidence indicated that conventional and targeted therapies could affect tumor-associated immune responses and increase the effectiveness of immunotherapy. However, the effects of Niraparib, one of the poly (ADP) ribose polymerase (PARP) inhibitors, on the immune response remains unclear. Delineating the crosstalk between cytotoxic anticancer agents and cancer-associated immunity may lead to more efficient combinatorial strategies. Methods Programmed death ligand 1 (PD-L1) expression in human ovarian cancer cells after PARP inhibitors treatment was examined by western blotting (WB) and flow cytometry. The expression of poly ADP-ribose polymerase (PARP1), PD-L1, and CD8 in human ovarian cancer tissues was detected by immunohistochemistry(IHC). The effect of Niraparib and PD-L1 blockade in ovarian cancer progression was investigated in vivo. The changes of immune cells and cytokines in vitro and in vivo were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Changes of cGAS/STING signal pathway after Niraparib treatment were determined by WB, ELISA. Results Niraparib upregulated membrane PD-L1 and total PD-L1 expression in ovarian cancer cells and had a synergistic effect with PD-L1 blockade in vivo. In clinical patient samples, Niraparib augmented cytotoxic CD8+T cell proportion and function. In vivo and vitro, Niraparib can also increase the proportion of T cells and combined with PD-L1 blockade could further enhance the effect. Besides, Niraparib activated the cGAS-STING pathway, increasing the levels of cytokines such as CCL5 and CXCL10, which played a vital role in augmenting the infiltration and activation of cytotoxic T cells. Conclusions Niraparib could modulate the immune response via the activation of the cGAS/STING pathway, and combination with PD-L1 blockade could further enhance the effect. These results provide a sound theoretical basis for clinical treatment.

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Anti-Müllerian hormone (AMH) autocrine signaling promotes survival and proliferation of ovarian cancer cells

Scientific Reports ◽

10.1038/s41598-021-81819-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Maëva Chauvin ◽

Véronique Garambois ◽

Pierre-Emmanuel Colombo ◽

Myriam Chentouf ◽

Laurent Gros ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Growth ◽

Cell Viability ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Clonogenic Survival ◽

Ovarian Cancer Cells ◽

Physiological Range

AbstractIn ovarian carcinoma, anti-Müllerian hormone (AMH) type II receptor (AMHRII) and the AMH/AMHRII signaling pathway are potential therapeutic targets. Here, AMH dose-dependent effect on signaling and proliferation was analyzed in four ovarian cancer cell lines, including sex cord stromal/granulosa cell tumors and high grade serous adenocarcinomas (COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN). As previously shown, incubation with exogenous AMH at concentrations above the physiological range (12.5–25 nM) decreased cell viability. Conversely, physiological concentrations of endogenous AMH improved cancer cell viability. Partial AMH depletion by siRNAs was sufficient to reduce cell viability in all four cell lines, by 20% (OVCAR8 cells) to 40% (COV434-AMHRII cells). In the presence of AMH concentrations within the physiological range (5 to 15 pM), the newly developed anti-AMH B10 antibody decreased by 25% (OVCAR8) to 50% (KGN) cell viability at concentrations ranging between 3 and 333 nM. At 70 nM, B10 reduced clonogenic survival by 57.5%, 57.1%, 64.7% and 37.5% in COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN cells, respectively. In the four cell lines, B10 reduced AKT phosphorylation, and increased PARP and caspase 3 cleavage. These results were confirmed in ovarian cancer cells isolated from patients’ ascites, demonstrating the translational potential of these results. Furthermore, B10 reduced COV434-MISRII tumor growth in vivo and significantly enhanced the median survival time compared with vehicle (69 vs 60 days; p = 0.0173). Our data provide evidence for a novel pro-survival autocrine role of AMH in the context of ovarian cancer, which was targeted therapeutically using an anti-AMH antibody to successfully repress tumor growth.

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Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920913798 ◽

2020 ◽

Vol 12 ◽

pp. 175883592091379 ◽

Cited By ~ 3

Author(s):

David W. Doo ◽

Selene Meza-Perez ◽

Angelina I. Londoño ◽

Whitney N. Goldsberry ◽

Ashwini A. Katre ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Immune Response ◽

T Cells ◽

T Cell ◽

Tumor Growth ◽

Expression Patterns ◽

Prolonged Survival ◽

Ovarian Cancer Cells ◽

Gene Expression Patterns

Background: The Wnt/β-catenin pathway is linked to tumorigenesis in a variety of tumors and promotes T cell exclusion and resistance to checkpoint inhibitors. We sought to determine whether a small molecule inhibitor of this pathway, WNT974, would impair tumor growth, affect gene expression patterns, and improve the immune response in human and murine ovarian cancer models. Methods: Human ovarian cancer cells were treated with WNT974 in vitro. RNAseq libraries were constructed and differences in gene expression patterns between responders and nonresponders were compared to The Cancer Genome Atlas (TCGA). Mice with subcutaneous or intraperitoneal ID8 ovarian cancer tumors were treated with WNT974, paclitaxel, combination, or control. Tumor growth and survival were measured. Flow cytometry and β-TCR repertoire analysis were used to determine the immune response. Results: Gene expression profiling revealed distinct signatures in responders and nonresponders, which strongly correlated with T cell infiltration patterns in the TCGA analysis of ovarian cancer. WNT974 inhibited tumor growth, prevented ascites formation, and prolonged survival in mouse models. WNT974 increased the ratio of CD8+ T cells to T regulatory cells (Tregs) in tumors and enhanced the effector functions of infiltrating CD4+ and CD8+ T cells. Treatment also decreased the expression of inhibitory receptors on CD8+ T cells. Combining WNT974 with paclitaxel further reduced tumor growth, prolonged survival, and expanded the T cell repertoire. Conclusions: These findings suggest that inhibiting the Wnt/β-catenin pathway may have a potent immunomodulatory effect in the treatment of ovarian cancer, particularly when combined with paclitaxel.

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Adenosine Analogues as Opposite Modulators of the Cisplatin Resistance of Ovarian Cancer Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190118113201 ◽

2019 ◽

Vol 19 (4) ◽

pp. 473-486 ◽

Cited By ~ 1

Author(s):

Katarzyna Bednarska-Szczepaniak ◽

Damian Krzyżanowski ◽

Magdalena Klink ◽

Marek Nowak

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Biology ◽

Immune Cell ◽

Immunosuppressive Agents ◽

Cell Activity ◽

Ovarian Cancer Cells ◽

Adenosine Analogues

Background: Adenosine released by cancer cells in high amounts in the tumour microenvironment is one of the main immunosuppressive agents responsible for the escape of cancer cells from immunological control. Blocking adenosine receptors with adenosine analogues and restoring immune cell activity is one of the methods considered to increase the effectiveness of anticancer therapy. However, their direct effects on cancer cell biology remain unclear. Here, we determined the effect of adenosine analogues on the response of cisplatinsensitive and cisplatin-resistant ovarian cancer cells to cisplatin treatment. Methods: The effects of PSB 36, DPCPX, SCH58261, ZM 241385, PSB603 and PSB 36 on cisplatin cytotoxicity were determined against A2780 and A2780cis cell lines. Quantification of the synergism/ antagonism of the compounds cytotoxicity was performed and their effects on the cell cycle, apoptosis/necrosis events and cisplatin incorporation in cancer cells were determined. Results: PSB 36, an A1 receptor antagonist, sensitized cisplatin-resistant ovarian cancer cells to cisplatin from low to high micromolar concentrations. In contrast to PSB 36, the A2AR antagonist ZM 241385 had the opposite effect and reduced the influence of cisplatin on cancer cells, increasing their resistance to cisplatin cytotoxicity, decreasing cisplatin uptake, inhibiting cisplatin-induced cell cycle arrest, and partly restoring mitochondrial and plasma membrane potentials that were disturbed by cisplatin. Conclusion: Adenosine analogues can modulate considerable sensitivity to cisplatin of ovarian cancer cells resistant to cisplatin. The possible direct beneficial or adverse effects of adenosine analogues on cancer cell biology should be considered in the context of supportive chemotherapy for ovarian cancer.

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CC Chemokine Ligand 7 Derived from Cancer-Stimulated Macrophages Promotes Ovarian Cancer Cell Invasion

Cancers ◽

10.3390/cancers13112745 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2745

Author(s):

Miran Jeong ◽

Yi-Yue Wang ◽

Ju-Yeon Choi ◽

Myong-Cheol Lim ◽

Jung-Hye Choi

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Invasion ◽

Ovarian Cancer Cell ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Cancer Cell Invasion ◽

Cc Chemokine ◽

Chemokine Ligand

In the tumor microenvironment, macrophages have been suggested to be stimulated by tumor cells, becoming tumor-associated macrophages that promote cancer development and progression. We examined the effect of these macrophages on human ovarian cancer cell invasion and found that conditioned medium of macrophages stimulated by ovarian cancer cells (OC-MQs) significantly increased cell invasion. CC chemokine ligand 7 (CCL7) expression and production were significantly higher in OC-MQs than in the control macrophages. Peritoneal macrophages from patients with ovarian cancer showed higher CCL7 expression levels than those from healthy controls. Inhibition of CCL7 using siRNA and neutralizing antibodies reduced the OC-MQ-CM-induced ovarian cancer cell invasion. CC chemokine receptor 3 (CCR3) was highly expressed in human ovarian cancer cells, and a specific inhibitor of this receptor reduced the OC-MQ-CM-induced invasion. Specific signaling and transcription factors were associated with enhanced CCL7 expression in OC-MQs. CCL7-induced invasion required the expression of matrix metalloproteinase 9 via activation of extracellular signal-related kinase signaling in human ovarian cancer cells. These data suggest that tumor-associated macrophages can affect human ovarian cancer metastasis via the CCL7/CCR3 axis.

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Targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies

Scientific Reports ◽

10.1038/s41598-021-82686-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Marina Stasenko ◽

Evan Smith ◽

Oladapo Yeku ◽

Kay J. Park ◽

Ian Laster ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Cancer Therapeutics ◽

Ca 125 ◽

Ovarian Cancer Cells ◽

Carbohydrate Binding ◽

Matrigel Invasion ◽

Galectin 3

AbstractThe lectin, galectin-3 (Gal3), has been implicated in a variety of inflammatory and oncogenic processes, including tumor growth, invasion, and metastasis. The interactions of Gal3 and MUC16 represent a potential targetable pathway for the treatment of MUC16-expressing malignancies. We found that the silencing of Gal3 in MUC16-expressing breast and ovarian cancer cells in vitro inhibited tumor cell invasion and led to attenuated tumor growth in murine models. We therefore developed an inhibitory murine monoclonal anti–Gal3 carbohydrate-binding domain antibody, 14D11, which bound human and mouse Gal3 but did not bind human Galectins-1, -7, -8 or -9. Competition studies and a docking model suggest that the 14D11 antibody competes with lactose for the carbohydrate binding pocket of Gal3. In MUC16-expressing cancer cells, 14D11 treatment blocked AKT and ERK1/2 phosphorylation, and led to inhibition of cancer cell Matrigel invasion. Finally, in experimental animal tumor models, 14D11 treatment led to prolongation of overall survival in animals bearing flank tumors, and retarded lung specific metastatic growth by MUC16 expressing breast cancer cells. Our results provide evidence that antibody based Gal3 blockade may be a viable therapeutic strategy in patients with MUC16-expressing tumors, supporting further development of human blocking antibodies against Gal3 as potential cancer therapeutics.

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PD-L1 regulates tumorigenesis and autophagy of ovarian cancer by activating mTORC signaling

Bioscience Reports ◽

10.1042/bsr20191041 ◽

2019 ◽

Vol 39 (12) ◽

Cited By ~ 1

Author(s):

Hongmin Gao ◽

Juan Zhang ◽

Xiaohong Ren

Keyword(s):

Ovarian Cancer ◽

Immune Response ◽

Cancer Cells ◽

Clinical Significance ◽

Tumour Cell ◽

Normal Tissue ◽

Ovarian Tumour ◽

Ovarian Cancer Cells ◽

Adjacent Normal Tissue ◽

Novel Strategy

Abstract PD-L1 is a well-known immune co-stimulatory molecule that regulates tumour cell escape from immunity by suppressing the immune response. However, the clinical significance of PD-L1 in the progression of ovarian cancer is unclear. Our study demonstrated that PD-L1 is up-regulated in ovarian tumour tissue compared with its expression level in adjacent normal tissue. Furthermore, we confirmed that PD-L1 increases the proliferation of cancer cells by activating the AKT-mTORC signalling pathway, which is also enhanced by the expression of S6K, the substrate of mTORC. In addition, PD-L1 promotes the autophagy of ovarian cancer cells by up-regulating the expression of BECN1, a crucial molecule involved in the regulation of autophagy. In conclusion, PD-L1 may provide a target for the development of a novel strategy for the treatment of ovarian cancer.

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STK3 Suppresses Ovarian Cancer Progression by Activating NF-κB Signaling to Recruit CD8+ T-Cells

Journal of Immunology Research ◽

10.1155/2020/7263602 ◽

2020 ◽

Vol 2020 ◽

pp. 1-17

Author(s):

Xiangyu Wang ◽

Fengmian Wang ◽

Zhi-Gang Zhang ◽

Xiao-Mei Yang ◽

Rong Zhang ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Proliferation ◽

T Cells ◽

Tumor Growth ◽

Cd8 T Cells ◽

Gene Set Enrichment Analysis ◽

Ovarian Cancer Cells ◽

And Migration

Serine/threonine protein kinase-3 (STK3) is a critical molecule of the Hippo pathway but little is known about its biological functions in the ovarian cancer development. We demonstrated the roles of STK3 in ovarian cancer. Existing databases were used to study the expression profile of STK3. STK3 was significantly downregulated in OC patients, and the low STK3 expression was correlated with a poor prognosis. In vitro cell proliferation, apoptosis, and migration assays, and in vivo subcutaneous xenograft tumor models were used to determine the roles of STK3. The overexpression of STK3 significantly inhibited cell proliferation, apoptosis, and migration of ovarian cancer cells in vitro and tumor growth in vivo. Bisulfite sequencing PCR analysis was performed to validate the methylation of STK3 in ovarian cancer. RNA sequencing and gene set enrichment analysis (GSEA) were used to compare the transcriptome changes in the STK3 overexpression ovarian cancer and control cells. The signaling pathway was analyzed by western blotting. STK3 promoted the migration of CD8+ T-cells by activating nuclear transcription factor κB (NF-κB) signaling. STK3 is a potential predictor of OC. It plays an important role in suppressing tumor growth of ovarian cancer and in chemotaxis of CD8+ T-cells.

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