Anna Pawłowska-Łachut

circRNAs in Endometrial Cancer—A Promising Biomarker: State of the Art

Endometrial cancer (EC) is one of the most common malignant tumors among women in the 21st century, whose mortality rate is increasing every year. Currently, the diagnosis of EC is possible only after a biopsy. However, it is necessary to find a new biomarker that will help in both the diagnosis and treatment of EC in a non-invasive way. Circular RNAs (circRNAs) are small, covalently closed spherical and stable long non-coding RNAs (lncRNAs) molecules, which are abundant in both body fluids and human tissues and are expressed in various ways. Considering the new molecular classification of EC, many studies have appeared, describing new insights into the functions and mechanisms of circRNAs in EC. In this review article, we focused on the problem of EC and the molecular aspects of its division, as well as the biogenesis, functions, and diagnostic and clinical significance of circRNAs in EC.

Current Understanding on Why Ovarian Cancer Is Resistant to Immune Checkpoint Inhibitors

The standard treatment of ovarian cancer (OC) patients, including debulking surgery and first-line chemotherapy, is unsatisfactory because of recurrent episodes in the majority (~70%) of patients with advanced OC. Clinical trials have shown only a modest (10–15%) response of OC individuals to treatment based on immune checkpoint inhibitors (ICIs). The resistance of OC to therapy is caused by various factors, including OC heterogeneity, low density of tumor-infiltrating lymphocytes (TILs), non-cellular and cellular interactions in the tumor microenvironment (TME), as well as a network of microRNA regulating immune checkpoint pathways. Moreover, ICIs are the most efficient in tumors that are marked by high microsatellite instability and high tumor mutation burden, which is rare among OC patients. The great challenge in ICI implementation is connected with distinguishing hyper-, pseudo-, and real progression of the disease. The understanding of the immunological, molecular, and genetic mechanisms of OC resistance is crucial to selecting the group of OC individuals in whom personalized treatment would be beneficial. In this review, we summarize current knowledge about the selected factors inducing OC resistance and discuss the future directions of ICI-based immunotherapy development for OC patients.

Prognostic and Clinical Value of Interleukin 6 and CD45 + CD14 + Inflammatory Cells with PD‐L1 + /PD‐L2 + Expression in Patients with Different Manifestation of Ovarian Cancer

Ovarian cancer (OC) is one of the deadliest gynecological cancers. Recent studies suggest a crucial role of inflammatory immune system cells in the progression and metastasis of OC. The understanding of inflammatory mechanisms is pivotal for the selection of a biomarker that allows the differentiation between malignant and benign tumors, monitoring the progression of the disease, and identification of patients that will respond to implemented treatment. Our study is aimed at evaluating the profile of IL‐6 in the plasma and peritoneal fluid (PF) of patients with various clinical manifestations of OC ( n = 78). We also examined the relationship between IL‐6 and PD‐L1/PD‐L2 positive CD45 + CD14 + inflammatory cell (MO/MA) levels in three OC environments (TME): peripheral blood (PB), PF, and tumor (TT) and their clinical and prognostic relevance in OC patients. The expression of PD‐L1/PD‐L2 molecules was analyzed by flow cytometry. The IL‐6 levels were determined by ELISA. We found an elevated level of PD‐L1/PD‐L2 positive MO/MA in TT compared to PB ( p < 0.0001). Significantly higher ( p < 0.0001) levels of IL‐6 were observed in PF of the OC patients than in the benign ovarian tumor group ( n = 31). Additionally, we found higher IL‐6 levels in PF than in the plasma of the OC patients. Interestingly, accumulation of IL‐6 was observed in PF of patients with low‐differentiated OC and correlated with worse prognosis. Moreover, we observed correlations between the level of IL‐6 and CD45 + CD14 + cells and between CD45 + CD14 + PD‐L1 + cells and the IL‐6 level in PF. For the first time, we discovered that the higher percentage of CD45 + CD14 + PD‐L2 + cells in PF predicts better survival of OC patients. Our study suggests that CD45 + CD14 + PD‐L2 + cells and IL‐6 may be predictive biomarkers for OC patients. Understanding how the composition of TME changes during OC development and progression is a prerequisite for projecting new therapeutic strategies. Overall, further validation research is warranted.

Clinical Significance of Tie-2-Expressing Monocytes/Macrophages and Angiopoietins in the Progression of Ovarian Cancer—State-of-the-Art

Tumour growth and metastasis are specific to advanced stages of epithelial ovarian cancer (EOC). Tumour angiogenesis is an essential part of these processes. It is responsible for providing tumours with nutrients, metabolites, and cytokines and facilitates tumour and immune cell relocation. Destabilised vasculature, a distinctive feature of tumours, is also responsible for compromising drug delivery into the bulk. Angiogenesis is a complex process that largely depends on how the tumour microenvironment (TME) is composed and how a specific organ is formed. There are contrary reports on whether Tie-2-expressing monocytes/macrophages (TEMs) reported as the proangiogenic population of monocytes have any impact on tumour development. The aim of this paper is to summarise knowledge about ovarian-cancer-specific angiogenesis and the unique role of Tie-2-expressing monocytes/macrophages in this process. The significance of this cell subpopulation for the pathophysiology of EOC remains to be investigated.

Clinical and Prognostic Value of Antigen-Presenting Cells with PD-L1/PD-L2 Expression in Ovarian Cancer Patients

The latest literature demonstrates the predominant role of the programmed cell death axis (PD-1/PD-L1/PD-L2) in ovarian cancer (OC) pathogenesis. However, data concerning this issue is ambiguous. Our research aimed to evaluate the clinical importance of PD-L1/PD-L2 expression in OC environments. We evaluated the role of PD-L1/PD-L2 in OC patients (n = 53). The analysis was performed via flow cytometry on myeloid (mDCs) and plasmacytoid dendritic cells (pDCs) and monocytes/macrophages (MO/MA) in peripheral blood, peritoneal fluid (PF), and tumor tissue (TT). The data were correlated with clinicopathological characteristics and prognosis of OC patients. The concentration of soluble PD-L1 (sPD-L1) and PD-1 in the plasma and PF were determined by ELISA. We established an accumulation of PD-L1+/PD-L2+ mDCs, pDCs, and MA in the tumor microenvironment. We showed an elevated level of sPD-L1 in the PF of OC patients in comparison to plasma and healthy subjects. sPD-L1 levels in PF showed a positive relationship with Ca125 concentration. Moreover, we established an association between higher sPD-L1 levels in PF and shorter survival of OC patients. An accumulation of PD-L1+/PD-L2+ mDCs, pDCs, and MA in the TT and high sPD-L1 levels in PF could represent the hallmark of immune regulation in OC patients.