Novel miRNAs as Potential Regulators of PD-1/PD-L1 Immune Checkpoint, and Prognostic Value of MIR9-1 and MIR124-2 Methylation in Ovarian Cancer

The incidence of ovarian cancer, which has had a poor prognosis, is increasing annually. Currently, the prognosis is expected to improve with the use of molecular-targeted drugs and immune checkpoint inhibitors as maintenance therapies after the first-line chemotherapy. The GOG218 and ICON7 studies reported the usefulness of bevacizumab and the SOLO-1 and PRIMA (A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy) studies have reported the usefulness of olaparib and niraparib, respectively. The ATHENA study investigating the usefulness of rucaparib is currently ongoing. Although clinical studies of immune checkpoint inhibitors are lagging in the field of gynecology, many clinical studies using programmed death cell-1 (PD-1) and PD-1 ligand 1 (PD-L1) antibodies are currently ongoing. Some biomarkers have been identified for molecular-targeted drugs, but none have been identified for immune checkpoint inhibitors, which is a challenge that should be addressed in the future.

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Prognostic value of immune-related cells and genes in the tumor microenvironment of ovarian cancer, especially CST4

Life Sciences ◽

10.1016/j.lfs.2021.119461 ◽

2021 ◽

pp. 119461

Author(s):

Shuang Wang ◽

Caixia Wang ◽

Ouxuan Liu ◽

Yuexin Hu ◽

Xiao Li ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Microenvironment ◽

Prognostic Value

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Comprehensive Analysis of the Expression of Key Genes Related to Hippo Signaling and Their Prognosis Impact in Ovarian Cancer

Diagnostics ◽

10.3390/diagnostics11020344 ◽

2021 ◽

Vol 11 (2) ◽

pp. 344

Author(s):

Paul Kubelac ◽

Cornelia Braicu ◽

Lajos Raduly ◽

Paul Chiroi ◽

Andreea Nutu ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Progression ◽

Prognostic Value ◽

Prognostic Significance ◽

Expression Level ◽

Additional Patient ◽

Tumor Control ◽

Hippo Signaling ◽

Patient Cohort ◽

Qrt Pcr

The Hippo signaling pathway, one of the most conserved in humans, controlling dimensions of organs and tumor growth, is frequently deregulated in several human malignancies, including ovarian cancer (OC). The alteration of Hippo signaling has been reported to contribute to ovarian carcinogenesis and progression. However, the prognostic roles of individual Hippo genes in OC patients remain elusive. Herein we investigated the expression level and prognostic value of key Hippo genes in OC using online databases, followed by a qRT-PCR validation step in an additional patient cohort. Using the GEPIA database, we observed an increased level for TP53 and reduced expression level for LATS1, LATS2, MST1, TAZ, and TEF in tumor tissue versus normal adjacent tissue. Moreover, LATS1, LATS2, TP53, TAZ, and TEF expression levels have prognostic significance correlated with progression-free survival. The qRT-PCR validation step was conducted in an OC patient cohort comprising 29 tumor tissues and 20 normal adjacent tissues, endorsing the expression level for LATS1, LATS2, and TP53, as well as for two of the miRNAs targeting the TP53 gene, revealing miR-25-3p upregulation and miR-181c-5p downregulation. These results display that there are critical prognostic value dysregulations of the Hippo genes in OC. Our data demonstrate the major role the conserved Hippo pathway presents in tumor control, underlying potential therapeutic strategies and controlling several steps modulated by miRNAs and their target genes that could limit ovarian cancer progression.

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Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1712514114 ◽

2017 ◽

Vol 114 (51) ◽

pp. E10981-E10990 ◽

Cited By ~ 82

Author(s):

Meredith L. Stone ◽

Katherine B. Chiappinelli ◽

Huili Li ◽

Lauren M. Murphy ◽

Meghan E. Travers ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Microenvironment ◽

Immune Cells ◽

Immune Checkpoint ◽

Histone Deacetylase Inhibitors ◽

Unmet Need ◽

Tumor Burden ◽

Epigenetic Therapy ◽

Type I ◽

Type I Ifn

Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.

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