Clinicopathological Implications of Serum level of IL-27 in Endometrial Cancer Patients

& Objective: Endometrial cancer (EC) is the most prevalent gynecological malignancy in more developed countries. Multiple researches have been done about the role of IL -27 in different cancers that suggest a dual role for this cytokine. In the present study, we evaluated the serum level of IL-27 in endometrial cancer patients. We also investigated the correlations between serum levels of IL-27 and the demographic and clinicopathologic features of the patients.

& Methods: In this case-control study, 65 endometrial cancer patients and 58 sex-age-match healthy controls were investigated. Serum levels of IL -27 in both cases and the control group were assessed by a reliable and specific sandwich enzyme- linked immunosorbent assay (ELISA) kit and results were analyzed with SPSS.

We observed that the serum level of IL-27 in EC patients was dramatically higher than in the control group (P=0.003). Additionally, Higher grades of EC (grade II and III) showed higher IL-27 serum levels compared to the control (P=0.006 and P=0.01 respectively). No significant correlations between serum levels of IL -27 and lymph node involvement, tumor stage, tumor size, and demographic features of the patients were detected.

Our results showed that there is a statistically significant difference between serum levels of IL-27 in EC patients and controls. Therefore, the serum level of IL-27 may exert a role in the pathogenesis of endometrial carcinoma, although further studies are needed.

Cytokines, Endometrial cancer, Gynecological Malignancy, IL -27 Received: 2024/03/03; Accepted: 2024/07/14; Published Online: 10 Oct 2024; Use your device to scan and read the article online Corresponding Information: Mohammad Javad Fattahi, Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran Email: [email protected] Copyright © 2024, This is an original open-access article distributed under the terms of the Creative Commons Attribution-noncommercial 4.0 International License which permits copy and redistribution of the material just in noncommercial usages with proper citation.

Endometrial carcinoma (EC), a tumor originating in the uterine epithelium, is the most prevalent gynecological malignancy in the United States and Western countries (1). EC incidence rate is increasing, and multiple factors are involved, including increasing in life expectancies and obesity (2). EC can classify into two different groups: type I which occurs in the younger, pre -menopausal population is hormone - dependent and has a good prognosis while Type II is more common in older, post -menopausal women and is considered estrogen -independent. Type II EC is usually more aggressive with a very poor prognosis (3, 4). The main risk factors of EC are old age (over 55 years), estrogens exposure (endogenous or exogenous), obesity, diabetes, early menarche; nulliparity, late - onset menopause, and tamoxifen use (5 -8). Although the etiology of EC is not clear, it is now widely understood that genetic and environmental factors interact to impact the risk of developing EC (9). Inflammation can also contribute to EC progression (10). In the inflammatory process, cytokines play a substantial role as key mediators. The role of different kinds of cytokines including IL -27 is extensively investigated in different kinds of diseases and immune conditions. Several studies on the role of IL -27 in clinical disorders have shown that this cytokine can influence the pathogenesis of chronic diseases such as coronary artery disease (11), Parkinson’s disease (12), rheumatoid arthritis (RA) (13), tuberculosis (TB) (14), viral infections (15, 16), systemic lupus erythematosus (SLE) (17), as well as cancers (18, 19). IL-27 is a new heterodimeric cytokine related to the IL-6/IL-12 family, which was identif ied in 2002 by Pflanz et al (20). Epstein -Barr Virus-induced gene 3 protein (EBI3) and IL -27p28 (IL-27A) are subunits of IL-27. IL -27 binds to a heterodimeric receptor 659 L-27 Serum Levels in Endometrial Cancer Volume 9, November – December 2024 Journal of Obstetrics, Gynecology and Cancer Research consisting of gp130 and IL -27 receptor alpha (IL - 27Ra) also known as WSX1 and activates the JAK/STAT signaling pathway (21 -23). iAntigen- presenting cells (APCs) such as macrophages (MQs) and dendritic cells (DCs) as well as epithelial cells are the main producers of IL-27 (24). IL-27 has a complex effect and various research have revealed that it has a dual role in innate and adaptive immunity (25). This cytokine has been discovered to have immune -enhancing properties via increasing T cell and natural killer (NK) cell proliferation as well as IFN- γ generation (20). However, by limiting T cel l responses, IL-27 may act as a regulatory cytokine (26). It has been also reported that the IL -27 can promote Treg development or conversion, induce IL -10 in T helper cells (Th1, Th2, and Th17), and increase the expression of PD-L1 on immune and nonimmune cells (27). The impact of IL -27 on cancers is controversial. IL-27 administration has been demonstrated to have some effects on the immunological pathways that contribute to tumor elimination, while sometimes IL - 27 effects are in favor of tumorigenesis (27, 28). In this study, we aimed to examine the serum level of IL-27 in EC patients to determine its possible role in EC pathogenesis. In addition, the association between clinicopathologic and demographic factors of patients and serum level of IL-27 was evaluated.

2.1 Study population The present study included 65 cases with clinical and histopathological diagnosis of EC who had no previous history of additional neoplasms and autoimmune diseases. According to pathological typing, all the selected EC patients had endometrioid adenocarcinoma. Sampling was done before any kind of treatment including chemo -radiation therapy, immunotherapy, or surgery. They were recruited from the gynecology clinic of Motahari and Faghihi hospital affiliated with Shiraz University of Medical Sciences (Shiraz, Iran). 58 age-matched healthy women without any evidence or history of genetic disorders, autoimmune diseases, cancer, and infectious diseases at least for the past four months were randomly selected from Shiraz Blood Transfusion Organization and considered as the control group. To determine the tumor stage and grade, we used the International Federation of Gynecology and Obstetrics (FIGO) classification. The research ethics committee of Shiraz University of Medical Sciences approved the study (IR.sums.med.rec.1399.91), and all participants provided written informed permission before participating in the study. 2.2 ELISA analysis Three millilitres of the peripheral blood was obtained from both case and control groups; the sera were separated by centrifugati on and stored at - 70◦C until analysis. Serum levels of IL-27 in all participants were measured by a specific sandwich ELISA kit (BT laboratory, Shanghai, China) according to the manufacturer’s procedures and using the standard concentrations of IL -27, prov ided by BT laboratory, and presented as pg/ml. 2.3 Statistical analysis For data analysis, Statistical Package for Social Sciences (SPSS, version 20.0; IBM Corporation, USA) was used. The Kolmogorov- Smirnov and Shapiro - Wilk tests were performed to assess t he normality of data. Variables with normal distribution are presented as mean ± (SD), otherwise as median and first and third interquartile ranges (IQR). Appropriate parametric (T - test, Anova) and non -parametric ( Mann–Whitney U - test, Kruskal –Wallis), Chi-square, and Fisher's exact tests were used for comparison between groups. Furthermore, Spearman's Rho test was used to analyze the possible effect of demographic features such as body mass index, menarche age, and menopause age on the serum level of IL -27 in patients. We also calculated the area under the ROC curve (AUC) to evaluate the utility of IL-27 in distinguishing EC from normal conditions, and the optimal cut-off value for IL- 27, additionally its specificity and sensitivity were measured. In the present study, P values of 0.05 or less were considered statistically significant.

In the present study, a total number of 65 EC patients and 58 age -matched healthy women as the control group were evaluated. The age range was between 30 and 86 years in EC patients, with a mean age of 56.5±11.48. In the control group, the age range was between 26 and 74 years with a mean age of 52.34±10.78. There was no significant difference in the mean age between EC patients and controls (p>0.05). Regarding tumor grades, 31 cases (47.7%) suffered from grade I, 20 cases (30.8%) from grade II, and 14 cases (21.5%) from grade III of the tumor. The baseline clinicopathologic features of patients and their associations with serum levels of IL -27 are pre sented in Table 1. No statistically significant relationship was observed between serum levels of IL -27 and patient’s age (P=0.14), tumor size (P=0.54), tumor stage (P=0.79) and lymph node involvement (P=0.47) (Table 1). The serum levels of IL-27 in patients and the control group were 265.80 (196.50- 346.60) pg/ml and 204.80 (127.80-270.70) pg/ml respectively, indicating a significant difference (P=0.003) (Figure 1). According to the FIGO classification, patients were categorized into three different groups (grade I, II, and III) and the level of IL-27 was measured separately in each group and compared to the control ( Figure 2 ). The serum levels of IL -27 in the group with grade I of EC was 232.60 (176.93-325.09) pg/ml and in the Control group Fatemeh Sedaghat et al. 660 Volume 9, November – December 2024 Journal of Obstetrics, Gynecology and Cancer Research was 204.80(127.80- 270.70) pg/ml, indicating no statistically significant differences (P =0.10). While in patients with grade II, serum concentration of IL -27 was 271.22(216.84- 346.64) pg/ml which showed significant differences in comparison with the control (P=0.006). In addition to patients with grade III of EC had statistically higher serum levels of IL -27 in comparison with the control group [271.10 (228.20- 467.40) versus 204.8 (127.80- 270.70) pg/ml respectively, P=0.01]. Regarding different EC grades, there were no significant differences between grade I versus II (P=0.31), grade I versus III (P=0.35), or grade II versus III (P=0.88) (Table 2). To determine relation between IL -27 serum levels and demographic factors such as body mass index (BMI), menarche age and menopause age, Spearman's Rho test was used which showed no substantial relationships between serum levels of IL -27 and mentioned factors (P=0.48, P=0.95, P=0.51 respectively) (Table 3) The ROC curve assessment ( Figure 3) revealed an AUC = 0.657, and 95% CI: 0.560 – 0.755. The optimal cut-off point of IL -27 for this differentia tion was estimated to be 212.42 pg/ml yielding a specificity of 57% and a sensitivity of 70%. Table 1. Demographic and clinicopathologic features of endometrial cancer patients and their associations with serum levels of IL-27 Variables Number (valid percent) IL-27 serum level pg/ml P-value Age ≤60 N=38 (58.5%) 218.14(183.22-305.59) 0.14 >60 N=27 (41.5%) 274.36(200.02-388.85) Tumor size ≤ 3 cm N=39 (60%) 256.85(176.93-346.64) 0.54 ˃3 cm N=26 (40%) 283.24(196.63-355.40) Lymph node involvement yes N=26 (40%) 258.64(203.32-309.38) 0.47 No N=39 (60%) 268.52(191.30-426.56) Tumor Grade Grade I N=31 (47.7%) 232.60(176.93-325.09) 0.42 Grade II N=20 (30.8%) 271.22(216.84-346.64) Grade III N=14 (21.5%) 271.10(228.20– 467.40) Tumor Stage Stage I N=40 (61.5%) 273.64(178.29-356.79) 0.79 Stage II N=15 (23.1%) 258.37(191.74-312.14) Stage III N=10 (15.4%) 264.72(201.17-321.52) 661 L-27 Serum Levels in Endometrial Cancer Volume 9, November – December 2024 Journal of Obstetrics, Gynecology and Cancer Research Table 2. The IL-27 serum levels in different grades of Endometrial Cancer Grade Frequency IL-27 serum level P-value II VS I 20(30.8%) VS 31(47.7%) 271.22(216.84– 346.64) VS 232.60(176.93 – 325.09) 0.31 III VS I 14 (21.5%) VS 31 (47.7%) 271.10(228.20 – 467.40) VS 232.60(176.93 – 325.09) 0.35 III VS II 14 (21.5%) VS 20 (30.8%) 271.10(228.20– 467.40) VS 271.22(216.84 – 346.64) 0.88 Table 3. Correlation between demographic characteristics of endometrial cancer patients and serum IL-27 levels BMI Menarche age Menopause age Spearman's Rho 0.089 0.007 -0.1 correlation coefficient 0.48 0.95 0.51 P Figure 1. The serum levels of IL -27 in EC patients demonstrated a remarkable increase compared with the healthy control group. P=0.003 Fatemeh Sedaghat et al. 662 Volume 9, November – December 2024 Journal of Obstetrics, Gynecology and Cancer Research Figure 2. The IL-27 serum levels in different grades of Endometrial Cancer. Figure 3. Area under the ROC curve analysis to determine the value of IL-27 in predicting Endometrial Cancer.

In the present study, we observed that the serum level of IL -27 dramatically increased in EC patients compared to healthy control group. Furthermore, in higher grades (grade II and grade III) higher concentrations of IL -27 were detected in comparison with control group. Although, several studies revealed the immune - regulatory effect of IL -27 in cancers and autoimmune disorders, its exact function is still controversial and complex. In the last decade, our knowledge about IL - 27 has changed from a cytokine t hat just induced Th1 cell response to one that has a both pro- inflammatory and anti -inflammatory effect. It appears that in early phases of inflammation process IL -27 induces inflammatory reaction, while in the late phases, by influencing various immune ce lls, it returns the immune reaction to homeostasis (29). P =0.10 P=0.006 P=0.01 663 L-27 Serum Levels in Endometrial Cancer Volume 9, November – December 2024 Journal of Obstetrics, Gynecology and Cancer Research IL-27 was initially identified as a pro -inflammatory cytokine that promoted the development of Th1 cells from naïve T cells (20). On the other hand, in some circumstances IL -27 has a role in develop ment of induced regulatory T lymphocytes (iTreg) with high IL-10 production capability (30, 31) , as well as transformation of dendritic cells into immunosuppressive phenotype by induction of B7- H1 expression (32). Furthermore, IL -27 can promote IL - 10 producing Tr1 cells from both human and mouse T cells and act in a negative feedback process against pro- inflammatory immune responses to favor tumor growth (33, 34). Diakowska group observed that serum IL -27 levels in patients with gastro-esophageal cancer (GEC) is substantially higher in comparison with healthy controls and patients with benign diseases of the upper parts of gastrointestinal (GI) tract (18). Lu et al (19) revealed that breast cancer patients had higher levels of VEGF and IL-27 than healthy controls. In their study, the level of IL -27 was shown to be substantially associated to clinical stage (19) . In the study by the Gonin et al (35), evaluation of IL -27 expression in primary cutaneous melanoma samples revealed absence of IL -27 in benign pigment and non- invasive melanoma lesions, but high expression of IL -27 in primary invasive melanoma. They concluded that IL - 27 expression was correl ated with disease development, but not regression of tumor in melanoma (35). IL-27 has also been demonstrated to play a key role in antitumor activities. Hisada was the first one who investigated the antitumor effects of IL-27 Hisada et al (36). In C26 mur ine colon carcinoma model, the Hisada et al. discovered that IL -27 has significant capacities to promote tumor -specific antitumor function and protective immunity which is mediated by IFN-γ, CD8+Tcells and T -bet but not through STAT4 (36). The anticancer e ffects of IL -27 have been discovered to be mediated via direct tumor growth suppression, activation of NK cells, antibody - dependent T or NKT cell cytotoxicity, anti - angiogenesis effects and cyclooxygenase -2 (COX -2) inhibition (37). It has also been shown that IL-27 acts as an antitumor factor and suppresses tumor growth in various kinds of cancers including esophageal cancer (38) , acute myeloid leukemia (39) , colorectal cancer (40) , head and neck squamous cell carcinoma (HNSCC) (41), and lung carcinoma cell lines Ho et al (42). According to Sekar et al (43) study, apoptotic tumor cells inhibit DCs from developing cytotoxicity against living human tumor cells by inducing IL -27, therefore activating a Treg cell population (43). The role of IL-27 in gynecological diseases has been limitedly studied, and its exact function and mechanism is unknown. It has been found that by inducing IFN-γ, IL-6, IL-12, HLA class I expression, and STAT3 -mediated apoptosis while reducing NF - κB1, TLR4 and ovarian tumor cell growth, IL-27 can create an anticancer environment (44, 45). On the other hand, IL-27 may contribute to progression of ovarian cancer by increasing immune- regulatory molecules like Programmed Death -Ligand (PD -L) 1 and indoleamine 2, 3- dioxygenase (IDO) in a STAT1 and STAT3 dependent mechanism (46) . IL-27 could also play a role in endometriosis. Chang et al. showed that IL-27 secreted by endometrial stromal cells and MQs promotes the progression of endometriosis by promoting the differentiation of IL-10+T helper (Th)17 cells (47). Studies to find a reliable tumor marker to diagnose endometrial cancer are ongoing. On the other hand, there is still a long way to go to understand the exact role of IL -27 in endometrial cancer, so more investigations are needed.

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Clinicopathological Implications of Serum level of IL-27 in Endometrial Cancer Patients. J Obstet Gynecol Cancer Res. 2024;9(6):658- 66. Download citation: RIS | EndNote | Mendeley |BibTeX |