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

2019 ◽  
Vol 39 (12) ◽  
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.

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

Biomolecules ◽  
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.

scholarly journals Photodynamic Therapy Using a New Folate Receptor-Targeted Photosensitizer on Peritoneal Ovarian Cancer Cells Induces the Release of Extracellular Vesicles with Immunoactivating Properties

2020 ◽  
Vol 9 (4) ◽  
pp. 1185 ◽  
Author(s):  
Martha Baydoun ◽  
Olivier Moralès ◽  
Céline Frochot ◽  
Colombeau Ludovic ◽  
Bertrand Leroux ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
Photodynamic Therapy ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Immune Cells ◽  
Surgical Techniques ◽  
Ovarian Cancer Cells ◽  
The Impact

Often discovered at an advanced stage, ovarian cancer progresses to peritoneal carcinoma, which corresponds to the invasion of the serosa by multiple tumor implants. The current treatment is based on the combination of chemotherapy and tumor cytoreduction surgery. Despite the progress and standardization of surgical techniques combined with effective chemotherapy, post-treatment recurrences affect more than 60% of women in remission. Photodynamic therapy (PDT) has been particularly indicated for the treatment of superficial lesions on large surfaces and appears to be a relevant candidate for the treatment of microscopic intraperitoneal lesions and non-visible lesions. However, the impact of this therapy on immune cells remains unclear. Hence, the objective of this study is to validate the efficacy of a new photosensitizer [pyropheophorbide a-polyethylene glycol-folic acid (PS)] on human ovarian cancer cells and to assess the impact of the secretome of PDT-treated cells on human peripheral blood mononuclear cells (PBMC). We show that PS, upon illumination, can induce cell death of different ovarian tumor cells. Furthermore, PDT using this new PS seems to favor activation of the immune response by inducing the secretion of effective cytokines and inhibiting the pro-inflammatory and immunosuppressive ones, as well as releasing extracellular vesicles (EVs) prone to activating immune cells. Finally, we show that PDT can activate CD4+ and CD8+ T cells, resulting in a potential immunostimulating process. The results of this pilot study therefore indicate that PS-PDT treatment may not only be effective in rapidly and directly destroying target tumor cells but also promote the activation of an effective immune response; notably, by EVs. These data thus open up good prospects for the treatment of micrometastases of intraperitoneal ovarian carcinosis which are currently inoperable.

Highly cytotoxic gold(i)-phosphane dithiocarbamate complexes trigger an ER stress-dependent immune response in ovarian cancer cells

2020 ◽  
Vol 49 (22) ◽  
pp. 7355-7363 ◽  
Author(s):  
Hai Van Le ◽  
Maria V. Babak ◽  
Muhammad Ali Ehsan ◽  
Muhammad Altaf ◽  
Lisa Reichert ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
Immune System ◽  
Er Stress ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
System P ◽  
Stress Dependent

Highly cytotoxic AuI-dithiocarbamate complexes were designed to induce severe integrative stress in ovarian cancer cells, leading to the surface exposure of calreticulin, which is a first step in the activation of immune system.

Defining the tumor cell: CA-MSC interactions which mediate ovarian cancer metastasis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18072-e18072
Author(s):  
Ester Goldfeld ◽  
Huda Atiya ◽  
Leonard Frisbie ◽  
Lan Gardner Coffman
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Protein Expression ◽  
Cancer Cells ◽  
Cell Lines ◽  
Western Blotting ◽  
Normal Tissue ◽  
Ovarian Cancer Cells ◽  
Rna Expression

e18072 Background: Carcinoma-associated mesenchymal stem cells (CA-MSCs) are mesenchymal stem cells (MSCs) within the tumor microenvironment (TME). We demonstrated that CA-MSCs promote ovarian cancer chemotherapy resistance through paracrine signaling with ovarian cancer cells, interact with ovarian cancer cells to form mixed-cellularity complexes which enhance metastasis, and arise from cancer cell and TME reprogramming of normal tissue MSCs. To identify mediators of the CA-MSC:tumor cell interaction, we investigated the role of tetraspanins, which are membrane-spanning proteins that have been implicated in cancer development and metastasis by influencing cell adhesion and cell-cell interactions. The tetraspanins CD9, CD81, CD151, and CD63 were identified as potential mediators of cell surface interactions between ovarian cancer cells and CA-MSCs through homo- and heterodimerization. Methods: Td-labeled OVCAR3 cancer cells were co-cultured with 3 patient-derived MSC (derived from normal tissue) and 3 patient-derived CA-MSC (derived from malignant tissue) cell lines. Flow cytometry was performed to measure surface protein expression of the tetraspanins CD9, CD81, CD151, and CD63, and was compared to control cells (not co-cultured) and their median fluorescence intensity (MFI). We next separated OVCAR3 cells co-cultured with MSCs or CA-MSCs using fluorescent activated cell sorting (FACS) based on Td expression. Following FACS, tetraspanin expression in OVCAR3 cells, MSCs, and CA-MSCs was assessed via qRT-PCR and western blotting, and compared to cell lines that were not co-cultured. Results: Flow cytometric analysis revealed an increase in MFI of CD9 and CD151 in co-cultured OVCAR3 cells, as well as CD81 and CD63 in co-cultured CA-MSCs and MSCs when compared to non-co-cultured matched cells. Increased RNA expression of CD9, CD151, and CD63 was seen in OVCAR3 cells that were co-cultured with CA-MSCs or MSCs when compared to non-co-cultured OVCAR3 cells. Increased RNA expression of CD81 and CD63 was noted in both co-cultured CA-MSCs and MSCs compared to non-co-cultured cells. Lastly, western blotting demonstrated increased protein expression of CD9 and CD151 in co-cultured OVCAR3 cells, as well as CD81 and CD63 in co-cultured CA-MSCs and MSCs compared to non-co-cultured matched cells. Conclusions: These results indicate that direct interactions between OVCAR3 cells and CA-MSCs or MSCs lead to overexpression of specific tetraspanins at the RNA and protein levels, implying that they may be facilitating tumor cell:CA-MSC and tumor cell:MSC binding.

scholarly journals Clinical significance of side population in ovarian cancer cells

Human Cell ◽  
2011 ◽  
Vol 24 (1) ◽  
pp. 9-12 ◽  
Author(s):  
Shinji Hosonuma ◽  
Yoichi Kobayashi ◽  
Satoshi Kojo ◽  
Haruka Wada ◽  
Ken-ichiro Seino ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Clinical Significance ◽  
Side Population ◽  
Ovarian Cancer Cells

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

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.

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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3698-3698
Author(s):  
Min Soon Cho ◽  
Omayra Gonzalez-Pagan ◽  
Karem Court Pinto ◽  
Anil Sood ◽  
Vahid Afshar-Kharghan
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
T Cells ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Checkpoint Inhibitors ◽  
Platelet Inhibition ◽  
Ovarian Cancer Cells ◽  
Tumor Bearing

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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