Immunotherapies based on PD-1/PD-L1 pathway inhibitors in ovarian cancer treatment

Pawłowska, Anna; Suszczyk, Dorota; Okła, Karolina; Barczyński, Bartłomiej; Kotarski, Jan; Wertel, Iwona

doi:10.1111/cei.13255

Cited by 38 publications

(44 citation statements)

References 80 publications

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“…Early diagnosis improves survival, but only 15% of OC cases are diagnosed at an early or localized stage. OC therefore presents a significant threat to the health of women worldwide ( 1 , 2 ). Although there are numerous chemotherapeutics available to treat OC and improve patient prognosis, the chemoresistance of OC remains a major obstacle for the successful treatment of OC ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

Downregulated expression levels of USP46 promote the resistance of ovarian cancer to cisplatin and are regulated by PUM2

Xu¹,

Zhang²,

Li³

2021

Mol Med Rep

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Ovarian cancer (OC) is a major contributor to cancer-related mortality in women. Despite numerous drugs being available for the treatment and improving the prognosis of OC, resistance to clinical chemotherapy remains a major obstacle for the treatment of advanced OC. Therefore, determining how to reverse the chemoresistance of OC has become a research hotspot in recent years. The present study aimed to reveal the potential mechanism of OC chemoresistance. Reverse transcription-quantitative PCR and western blot analysis were performed to detect the expression levels of Ubiquitin-specific peptidase 46 (USP46) and Pumilio 2 (PUM2) in OC. Cell viability and apoptosis were evaluated by Cell Counting Kit-8 assay and flow cytometry, respectively. The association between USP46 and PUM2 was assessed by RNA immunoprecipitation. The results of the present study revealed that the expression levels of USP46 which is associated with tumor progression, was downregulated, while PUM2 expression levels were upregulated in cisplatin (DDP)-resistant OC cells and patient tissues. The downregulation of USP46 expression levels in SKOV3 cells significantly inhibited cell apoptosis and increased cell viability. In SKOV3/DDP cells, the upregulation of USP46 expression levels notably suppressed cell viability and increased cell apoptosis. The results of the RNA immunoprecipitation chip assay demonstrated that PUM2 bound to USP46 and regulated its expression. Furthermore, following the knockdown of USP46 expression, the mRNA and protein expression levels of the cell apoptosis-related protein, Bcl-2, were upregulated, whereas the expression levels of caspase-3, caspase-9 and Bax were significantly downregulated. In addition, phosphorylated AKT expression levels were notably upregulated. Following the overexpression of USP46 in SKOV3/DDP cells, the opposite trends were observed. In SKOV3 cells, the knockdown of PUM2 could reverse the DDP resistance induced by small interfering RNA-USP46 as the expression levels of Bcl-2 were downregulated whereas those of caspase-3, caspase-9 and Bax were upregulated compared with the small interfering-USP46 group. Similarly, in SKOV3/DDP cells, the overexpression of PUM2 could reverse DDP sensitivity induced by the overexpression of USP46. In conclusion, the findings of the present study suggested that the downregulation of USP46 expression levels may promote DDP resistance in OC, which may be regulated by PUM2. Therefore, targeting PUM2/USP46 may be an effective way to reverse DDP resistance in OC.

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Section: Introductionmentioning

confidence: 99%

Downregulated expression levels of USP46 promote the resistance of ovarian cancer to cisplatin and are regulated by PUM2

Xu¹,

Zhang²,

Li³

2021

Mol Med Rep

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“…Tumor cells escape T-cell-mediated cellular cytotoxicity through regulating the programmed cell death (Pd)-1/Pd-ligand 1 (Pd-l1) pathway (26). Targeting the Pd-1/Pd-l1 pathway has emerged as a novel strategy in the treatment for a variety of malignancies (27)(28)(29). a previous study suggested that mir-140 exerts anti-osteosarcoma efficacy via targeting the immune checkpoint molecule Pd-l1 (30).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‑140 suppresses Helicobacter pylori‑positive gastric cancer growth by enhancing the antitumor immune response

Zhao

Liu

et al. 2019

Mol Med Report

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immune checkpoint blockade is a promising therapeutic strategy against various human malignancies. Micrornas (mirnas/mirs) regulate gene expression, by repressing mrna translation or promoting its degradation. The aim of the current study was to investigate the role and molecular mechanisms of mir-140 in Helicobacter pylori (Hp)-associated gastric cancer, and to examine its relationship with immune function in gastric cancer. Gastritis tissue samples from gastritis patients, and gastric cancer tissue samples from gastric cancer patients were collected for mir-140 expression detection. mir-140 expression was detected using reverse transcription-quantitative polymerase chain reaction, and protein expression was measured by western blotting. TargetScan and dual luciferase reporter assays were used to reveal the association between mir-140 and programmed cell death-ligand 1 (Pd-l1). BGc823 cell proliferation was detected by MTT assays. Ex vivo immune analysis by flow cytometry and ELISA were used to analyze immune function. it was demonstrated that mir-140 expression was significantly reduced in Hp-positive gastric cancer. PD-L1 was confirmed as a direct target of miR-140 in gastric cancer cells. In addition, PD-L1 expression was significantly increased in Hp-positive gastric cancer. overexpression of miR-140 significantly suppressed gastric cancer cell proliferation through regulating Pd-l1 expression. In vivo experiments also revealed that mir-140 markedly repressed tumor growth in the c57Bl/6 mice. Furthermore, it was determined that the tumor-suppressive role of mir-140 in gastric cancer was associated with increased cytotoxic cd8 + T cell and reduced myeloid-derived suppressive and regulatory T cell infiltration. miR-140 significantly prevented mammalian target of rapamycin signaling in gastric cancer cells. notably, these mir-140 overexpression-induced alterations were inhibited by PD-L1 plasmid. These findings indicated that miR-140 exerted an anti-gastric cancer effect by targeting immune checkpoint molecule Pd-l1. Thus, mir-140 may be a promising and novel immunotherapeutic target for gastric cancer treatment.

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“…Nevertheless, mAbs are currently in clinical trials, including Phase III, both in single and combined therapy. [34][35][36][37] Unfortunately, treatment based on mAbs inhibiting the PD-1/PD-L1 pathway is only efficient in a small group of OC patients. Moreover, OC treatment results are not as satisfying as in the case of other solid tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it is necessary to find predictive markers and understand the OC microenvironment to implement the treatment for precise groups of OC patients. 8,11,19,33,34 What is interesting, blood-borne metastases are rare in OC. The most common mechanism of metastasis is the release of cells into the peritoneal cavity from the primary tumor.…”

Section: Discussionmentioning

confidence: 99%

<p>Programmed Death-1 Receptor (PD-1) as a Potential Prognosis Biomarker for Ovarian Cancer Patients</p>

Pawłowska

Suszczyk

Tarkowski

et al. 2020

CMAR

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Aim: Ovarian cancer (OC) is one of the most lethal gynecological malignancies. Recent studies suggest a crucial role of the PD-1/PD-L1 pathway in OC pathogenesis. Therefore, our study aimed at evaluation of the clinical importance of PD-1 expression in ovarian cancer patients. Patients and Methods: In this study, we investigated the role of PD-1 in OC patients (n=50) by analyzing its expression on CD4 + and CD8 + T cells in three OC environments: peripheral blood (PB), peritoneal fluid (PF), and tumor (TT) as well as soluble PD-1 (sPD-1) in plasma and PF in terms of their clinical and prognostic significance. T cells with PD-1 expression were analyzed using flow cytometry. The concentration of sPD-1 was determined with the use of ELISA. Our research demonstrated differences in PD-1 expression on CD4 + and CD8 + T cells in the OC environments. Results: We found an elevated level of CD4 + PD-1 + T cells in tumor and PF, compared to PB. Additionally, we found the highest percentage of CD8 + PD-1 + in tumor, compared to PB and PF. The levels of sPD-1 were higher (p<0.0001) in plasma than in PF. For the first time, we discovered that the higher level of CD4 + PD-1 + T cells in the circulation and the higher sPD-1 level in plasma predict poor survival of OC patients. Conclusion: We suggest that PD-1 could be a predictive biomarker for OC patients and successful immunotherapy.

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Immunotherapies based on PD-1/PD-L1 pathway inhibitors in ovarian cancer treatment

Cited by 38 publications

References 80 publications

Downregulated expression levels of USP46 promote the resistance of ovarian cancer to cisplatin and are regulated by PUM2

Downregulated expression levels of USP46 promote the resistance of ovarian cancer to cisplatin and are regulated by PUM2

MicroRNA‑140 suppresses Helicobacter pylori‑positive gastric cancer growth by enhancing the antitumor immune response

<p>Programmed Death-1 Receptor (PD-1) as a Potential Prognosis Biomarker for Ovarian Cancer Patients</p>

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