Abstract
Objective: IL-16 has been described as a chemoattractant that activates macrophages, CD4+ T cells, eosinophils, dendritic cells, and monocytes, thus activating the secretion of inflammatory cytokines, including IL-15, IL-1β, and TNF-α. The present study aimed to investigate the IL-16 expression in the serum and elucidate IL-16 significance in the clinical assessment of epithelial ovarian cancer (EOC).
Methods: The study adopted an enzyme-linked immunosorbent assay (ELISA) to analyze the expressions of IL-16 in the serum derived from 80 EOC patients and 80 age-matched healthy controls. The association of IL-16 levels with EOC patients’ prognosis and clinical factors were determined. The receiver operator characteristic (ROC) analysis was done to determine the accuracy of serum IL-16 in EOC diagnosis.
Results: EOC patients demonstrated significantly increased serum IL-16 levels compared to the controls (192.4 ±54.27 pg/mL versus 90.5±41.27 pg/mL, P<0.001, respectively). Elevated IL-16 levels in the serum were remarkably linked with tumor size (P=0.001), FIGO (International Federation of Gynecology and Obstetrics) stage (P=0.001), recurrence (P=0.039), and metastasis of lymph node (P=0.029). Analysis of the Kaplan-Meier survival curve confirmed elevated IL-16 levels in serum is directly associated with poor overall survival (OS) (P=0.032) and progression-free survival (P=0.041). Assessment of univariate and multivariate results demonstrated IL-16 serum levels (HR: 2.996, 95%CI:1.313-4.231, P=0.006) were the independent EOC patients’ prognostic factors. Analyses of the ROC curve confirmed AUC of 0.781, 95% CI:0.639-0.923, P<0.001.
Conclusion: Elevated IL-16 serum levels are linked with poor prognosis in EOC patients, and IL-16 might be a promising biomarker for the prognosis of EOC among patients.
Epithelial ovarian cancer (EOC) is considered the deadliest gynecological tumor and the second leading global cause of death associated with cancers in women.1 As a result of non-specific and mild symptoms and the unavailability of effective screening techniques, the diagnosis of most patients is made at a late stage, leading to a 5-year overall survival rate below 50%.2 Even though EOC has established prognostic values of the clinical-pathological factors, and broad basic and clinical research efforts have been undertaken,3 the molecular mechanisms involved in its progression remain poorly understood. Consequently, identifying novel EOC diagnostic and predictive markers for early prediction, diagnosis, and treatment of the tumor remains a significant challenge.
Interleukin-16 (IL-16) is a cytokine that was initially described as a lymphocyte chemoattractant factor (LCF), and it is encoded by the IL-16 gene, which is found on chromosome 15q26.3.4 The cytokine consists of 631 amino acids. Furthermore, IL-16 is cleaved by caspase 3 to the phosphorylated IL-16 made up of the C-terminal 121 amino acids.5 Through the binding with the CD4 molecule, IL-16 activates macrophages, CD4+ T cells, eosinophils, dendritic cells, and monocytes, thus activating the inflammatory cytokines’ secretion, such as IL-15, IL-1β, and TNF-α. In addition, IL-16 plays a role of an immunomodulatory molecule, contributing to the regulation of the recruitment and activation of CD4+ cells at inflammation sites, and thus, the cytokine has a critical function to initiate or sustain the inflammatory response.6
Various reports have observed increased IL-16 levels in tumors harboring various types of cancers, including brain tumors,7 B-non-Hodgkin lymphoma8 and colorectal and gastric cancers.9 A genome-wide linkage investigation has previously reported IL-16 genotype might be an important marker for the prediction of prostate cancer.10
Even though these available clinical observations were made in other cancers, no clinical studies have reported the clinical significance of IL-16 in EOC. The present investigation, therefore, aimed at investigating the serum levels of IL-16 and its significance in EOC. The study finally assessed the association between the IL-16 expression in the serum and the prognosis status.
Materials and Methods
Patients Information and Ethical Statement
The study was carried out in the gynecology department of Ganzhou People’s Hospital of Jiangxi Province from May 2021 to December 2023. The study enrolled 80 newly diagnosed EOC patients and 80 healthy women. Determination of the sample size was done using the formula of a single population proportion by making the following assumptions: the proportion of EOC patients among people with epithelial ovarian cancer whose age >18 in Ganzhou People’s Hospital of Jiangxi Province was 12%. The precision 5%; 95% (Zα/2 = 1.96) confidence interval and 10% for non-response. In accordance, the total sample size was 80. A computer-generated simple random sampling technique was used to select the study participants from the hospital. EOC patients registration/care numbers were sorted and used in generating the random numbers. The inclusion criteria included the following: age 18 years and older, EOC patients newly diagnosed of stage I-IV cancer, completed either the primary or the interval debulking surgery, and the levels of preoperative serum CA-125 of at least 50 U/mL. Further inclusion criteria included absolute neutrophil count, platelets, and hemoglobin ≥1,500/uL, 100,000/uL, and 8.0 g/dL, respectively. Finally, the patients included had albumin level >3.5 g/dL and creatinine ≤1.5 times ULN. The exclusion criteria included patients below age 18 years, breastfeeding and lactating patients, or those with positive pregnancy resulting from a serum test. Other exclusion criteria included EOC patients undergoing any form of treatment, patients with active autoimmune infections including systemic lupus erythematosus, ulcerative colitis, rheumatoid arthritis, or multiple sclerosis. Patients with allergy or hypersensitivity to paclitaxel-carboplatin were also excluded.
The staging of EOC was established following the classification stipulated by the International Federation of Gynecologists and Obstetricians (FIGO). The histological type and grade classification was done following the World Health Organization guidelines. All patients were treated with the first-line chemotherapeutic regimen of a standard paclitaxel-carboplatin of six to eight courses. Retroperitoneal lymphadenectomy was not carried out in some cases involving aged patients, highly invasive surgical operations, severe hemorrhage, and severe complications. The median ages of EOC patients were 53 years (25-66), while the healthy women’s median ages were 51 years (range 24-65). Table 1 shows the patients’ clinic-pathological characteristics. The approval for the study was obtained from the Institutional Review Committee of Ganzhou People’s Hospital. All the participants provided written informed consent as stipulated in the guideline of the approving committee.
The correlations between the levels of IL-16 and clinic-pathologic characteristics in epithelial ovarian cancer patients
Plasma IL-16 Measurement
Samples of blood were drawn immediately on admission before the administration of any medical treatment or adjuvant. To obtain serum, the blood samples were centrifuged for 10 minutes at 3000g and 4°C. The samples were quickly frozen and kept at −80°C for use in the subsequent experiments. The levels of IL-16 in the serum were determined using a commercially acquired human IL-16 ELISA kit (D1600; R&D Systems, Minneapolis, USA) following the instructions of the manufacturer. In brief, pre-coating the human monoclonal antibody to the 96-well culture plate was first done. The plates were then incubated at room temperature for 2 hours to allow the binding of IL-16 to the immobilized antibody. The plates were washed to remove the unbound antibody. Later, IL-16-specific enzyme-conjugated was added to each well. The plates were then washed to eliminate the unattached enzyme and enzyme reagent. A substrate was added to each well to allow for the development of a color, proportional to the bound IL-16. The colored reaction intensity was determined at 450 nm with an automated ELISA reader. The results were expressed as ng/mL.
Statistical Analysis
Data were analyzed using IBM SPSS 26 software (SPSS, Chicago, IL, USA). Results were expressed as mean ± standard deviation (SD). The mean comparisons of various clinical and laboratory parameters were analyzed using t-test, Kruskal–Wallis test or Mann–Whitney U test, where appropriate. Overall survival (OS) was evaluated from the first admission to the EOC-related death date or the date of the last contact with the EOC patient or any member of the family. Calculation of the progression-free survival (PFS) was done from the admission to the disease progression dates. To distinguish the patients from the healthy controls, specificity, sensitivity, and the area under the curve (AUC) for serum IL-16 were assessed by analyzing receiver operator characteristics (ROC). Plotting of the survival curves was done with the Kaplan–Meier method and analyzed using the log-rank test. The IL-16 prognostic value was analyzed through univariate and multivariate Cox proportional hazard tests. P value <0.05 was regarded as statistically significant.
Results
Clinical Features of the Study Participants
In total, 80 patients and 80 age-matched healthy controls were involved in this study. The clinical features are shown in Table 1. No significant age difference was observed between the patients and the controls (P<0.05). In terms of histology, 39 (49.3%), 16 (20.6%), 7 (8.5%), 6 (7.4%), and 12 (14.2%) had serous, endometroid, clear cell, mucinous, and mixed tumor types without any particular histotype, respectively. In terms of histological grade, 22 (27.6%) had G1, 24 (29.8%) had G2, while 34 (42.6%) of the patients had G3 grade. There were 20 patients (24.6%) who had FIGO stage I, 18 (22.3%) had stage II, 36 (44.6%) had stage III, and 6 (8.5%) had stage IV EOC.
IL-16 is Elevated in the Serum of Patients with Epithelial Ovarian Cancer
The level of expression of IL-16 in patients with EOC, and the level in healthy controls was determined through the sandwich ELISA. According to our findings, the serum samples from the EOC patients contained significantly upregulated IL-16 levels (192.4±54.27 pg/mL) compared to the healthy controls (90.5±41.27 pg/mL) P<0.001, as shown in Figure 1A and Table 2. Further observations also confirmed the IL-16 levels in the serum were significantly elevated in the EOC patients, with highly progressed (Stage III-IV) EOC compared to the less severe (stage I-II) EOC, P<0.001, as shown in Figure 1B.
ELISA assessment of IL-16 expression in the serum of patients with epithelial ovarian cancer. (A) the levels of IL-16 in the serum of the EOC patients (n=80) and the healthy group (control) (n=80), range 25-66; (B) the IL-16 levels in the serum of patients with stages I-II (n=38) and III-IV (n=42). The data expression is in the form mean ± SD.
Mean IL-16 levels in the serum of EOC patient’s vs the healthy control group
IL-16 has a Positive Correlation with the Clinical Characteristics in EOC Patients
To determine the association of IL-16 and clinical features of EOC, serum level of IL-16 was analyzed in the various stages of EOC. Our observations confirmed increased IL-16 levels were associated with the increased size of tumor (P<0.001), higher FIGO stages (P<0.001), tumor recurrence (P<0.009), lymph node metastasis (P<0.008), and residual tumor size (P<0.004), as demonstrated in Table 1. Nevertheless, there were other clinical features that did not have any correlation with increased IL-16 levels. These clinical characteristics included histology, age, debulking surgery, histological grade, level of hemoglobin in the serum, levels of CA-125, and platinum sensitivity in relation to relapse.
Association Between IL-16 and EOC Clinical Outcomes
We additionally aimed at establishing the association of the overexpression of IL-16 with prognosis in the 80 EOC patients. As confirmed by the IL-16 median values in the serum, 201.5 pg/mL was picked as the cut-off value for categorizing patients into low (n=40) and high (n=40) levels of IL-16. The mean value of the low IL-16 was 121±44.71 pg/mL, while the mean value of the high IL-16 group was 174±36.32 pg/mL. The median follow-up time was 19 months (3-34 months). Our observations confirmed EOC patients with elevated IL-16 levels demonstrated poorer overall survival (OS) rate as shown in Figure 2A. In addition, the EOC patients with increased IL-16 levels had reduced progression-free survival compared to those with reduced IL-16 levels, as shown in Figure 2B. The mean overall time of survival for patients with elevated IL-16 levels was 20.6 months (95% CI:17.6-26.4). However, the mean overall time of survival for patients with low IL-16 levels was 27.4 months (95% CI:23.7-32.7). There was a statistically significant difference between the rate of overall survival (log-rank, P=0.031) and progression-free survival (log-rank, P=0.042) between the two groups.
Diagrams indicating Kaplan-Meier survival curves of correlation of serum IL-16 levels in the serum and survival. (A) overall survival of patients with EOC who show low or high IL-16 expression. (B) the progression-free survival of patients harboring low and high IL-16 expressions in the serum. The mean and median values of the serum IL-16 levels informed the selection of the cut-off value (136.4 pg/mL) for the categorization of patients to low (n=40) (mean = 121±44.71) or high (n=40) (mean= 174±36.32) IL-16 levels. The Log-rank test indicated that EOC patients with elevated IL-16 showed compromised overall survival (P=0.032) and progression-free survival (P=0.041) compared to the low IL-16 levels patients.
According to the analysis of univariate cox regression, overall survival had a significant relationship with the size of tumor, (P=0.001), FIGO stage (P=0.001), recurrence (P=0.009), lymph node metastasis (P=0.008), residual size of tumor (P=0.004) and serum IL-16 levels (P=0.001). Further, the multivariate cox assessment results ascertained that the independent prognosis factors for the prediction of poorer overall survival in the EOC patients are FIGO (HR: 2.996, 95% CI:1.313-4.231, P=0.006), recurrence (HR: 2.412, 95% CI:0.875-3.533, P=0.011), residual tumor size (HR:4.13, 95% CI:1.67-7.01, P=0.003), and serum IL-16 levels (HR:2.993, 95% CI:1.914-4.543, P=0.006), as shown in Table 3.
The uni- and multi-variate assessment of the EOC patients’ prognostic factors
The Possible Use of the Levels of IL-16 in the Diagnosis of EOC Patients
We later aimed to determine the accuracy of IL-16 in the diagnosis of EOC in patients. To this effect, analysis of ROC was done, and the finding, in this case, was to propose a possible use of the levels of serum IL-16 to screen for EOC in patients. Our findings confirmed that the IL-16 serum levels ROC curves demonstrated a better separation between the patients and the EOC-free controls (AUC=0.781, 95% CI: 0.639-0.923, P<0.001) (Figure 3A). The sensitivity was 82%, while the specificity was 88% at a cut-off value exceeding 136.4 pg/mL. In further analysis, the FIGO stage I-II had an AUC of 0.769, 95% CI: 0.622-0.916, P<0.001 (Figure 3B). The FIGO stage III-IV revealed an AUC of 0.825, 95% CI: 0.696-0.954, P<0.001, as shown in Figure 3C. According to these findings, the serum levels of IL-16 demonstrated accurate values, which can be used for diagnosing EOC in patients.
Analysis of receiver-operating characteristics (ROC) through the use of levels of IL-16 serum and FIGO staging to discriminate EOC patients. (A) ROC curves of serum IL-16 amounts demonstrated stronger discrimination between the EOC patients and the healthy group (AUC=0. 781, 95%CI: 0.639-0.923, P<0.001). (B) Determination of FIGO I-II AUC was 0.769 (95%CI: 0.622-0.916, P<0.001) and (C) FIGO III-IV staging indicated AUC of 0.825, 95%CI: 0.696-0.954, P<0.001.
Discussion
Interleukin 16 (IL-16) was mainly identified to be an essential factor needed for the recruitment and activation of lymphocytes. The precursor of IL-16 is activated intracellularly through a proteolytic cleavage prior to secretion. The IL-16 production is ensured by varying cells types including cells T lymphocytes, macrophages, mast cells, monocytes, dendritic cells, bronchial epithelium, and fibroblasts.11 The cytokine shows chemotactic features through their interaction with the lymphocytes-expressed CD4 and the mast cells-expressed CD9.12 IL-16 has been linked with various inflammatory diseases including asthma, Crohn’s disease, lung emphysema, and polyarthritis. Studies have also reported that IL-16 derived from neutrophils in premetastatic lungs enhances the seeding of breast tumor cells.13 However, no studies have investigated the concentration of IL-16 serum in EOC.
In the current work, the serum IL-16 levels were first examined in 80 patients harboring pathologically confirmed EOC diagnostic features and 80 age-matching healthy groups (controls). The assessment of IL-16 serum levels was determined by the sandwich ELISA assays. This investigation gives the first account for the significant IL-16 protein levels’ elevation in the EOC patients’ serum compared to the healthy controls. These findings are an indication that IL-16 might be potential marker for the progression of EOC. We later investigated the correlation between IL-16 serum levels and the EOC patients’ clinical factors. In our findings, the IL-16 serum expression was lower in the healthy controls but was significantly increased in the EOC patients. In addition, the increased IL-16 expression also reflected upregulated clinical characteristics including increased size of tumor, the highly progressed FIGO classification stages, tumor recurrence, lymph node metastasis, and the residual tumor size.
Clinically known factors including debulking surgery, histology, age, histology grade, level of serum hemoglobin, CA-125 level, relapse in platinum sensitivity, and lactate dehydrogenase level were confirmed to lack any correlation with the levels of serum IL-16. Assessment of correlation between the levels of serum IL-16 and EOC stage confirmed the IL-16 levels were remarkably differentiated between the early (FIGO I-II) compared to the advanced stage EOC patients (FIGO III-IV). The IL-16 expression levels were also positively linked with the metastasis of the lymph node, positive recurrence, and size of tumor. Residual tumor after surgery is the most defined EOC prognostic factor.14 Our findings confirmed a robust correlation between the IL-16 and the residual tumor. This observation suggests IL-16 may be a potential optimal rate of cyto-reduction prognostic marker. The findings of this study together indicate IL-16 might reduce the immune response against tumors, consequently contributing to tumor progression.
Our study agrees with numerous previous studies that linked IL-16 to inflammation and pathogenesis of various diseases. For instance, Christiana et al.15 confirmed the elevation of plasma IL-16 levels in acute myocardial infarction patients. Another study reported that IL-16 rs407111 G allele is remarkably linked with elevated risk of lung cancer among patients.16 In a pathological condition, activated fibroblast and endothelial cells, together with degranulated mast cells induce IL-16.17 In addition, previous reports have shown IL-16 is produced by the apoptotic immune cells.15
Our investigation also assessed the serum IL-16 levels’ effect on the prognosis of EOC patients. Analysis of the Kaplan-Meier survival demonstrated increased levels of IL-16 in serum directly correlate to unfavorable overall survival in patients with EOC. In addition, the analysis of ROC curve showed that the levels of serum IL-16 are indeed a potential EOC diagnostic biomarkers. The univariate and multivariate analysis confirmed the levels of serum IL-16 are factors that independently affect prognosis, confirming our hypothesis that IL-16 enhances the establishment and progression of EOC. These observations are in agreement with a previous investigation that confirmed IL-16 upregulation is correlated with unfavorable overall survival in gastric cancer patients with sarcopenia.18 Yang et al.19 also reported a 30.8% 5-year overall survival rate in elevated IL-16 gastric cancer patients but a 65% overall survival in gastric cancer patients with low IL-16 levels. The same study also revealed the Kaplan-Meier assessment confirmed a more prolonged overall survival for patients expressing low IL-16 levels but a significantly reduced survival for the group expressing high serum IL-16 levels.
In a particular in vivo study analyzing sera and the ovarian tissues in laying hens, the IL-16 serum levels were remarkably elevated in the hens with microscopic, early, and late ovarian cancer compared to the normal healthy group.20 This study also reported significantly increased IL-16 positive cells in the tumor-bearing ovaries compared to the healthy hens. The same study concluded that changes in the IL-16 serum levels are correlated with tumor-associated neo-angiogenesis and the development of tumors; hence, levels of serum IL-16 act as a biomarker of the ovarian tumor-associated neo-angiogenesis in the early stage of ovarian cancer.
Increased serum IL-16 in the serum observed among the EOC patients compared to the healthy group might be due to its role in pro-inflammation. Inflammation increases malignant transformation risks, and unregulated inflammation results in hypoxic conditions and the changed expression of pro-inflammatory cytokines such as IL-16,21 which also initiates further pro-inflammatory processes and immune cells chemotaxis to the inflamed site. Since ovulation is an inflammatory process, ovarian tissues experience continuous exposure to sustainable factors of inflammation, including IL-16. Elevated IL16 plasma levels result in the recruitment of various immune cells infiltrates into the tumors, eventually enhancing the progression of the tumors.11 Further, IL-16 induces the influx of macrophages into the sites of tumor growth, leading to an augmented tumor growth microenvironment.
Limitations
The limitation of this study is that it did not investigate the IL-16 expression in EOC patients’ tissues and lacked in vivo studies to investigate the association of IL-16 with other important tumor factors such as angiogenesis, migration, and invasion. In addition, this study did not consider or exclude the role of other confounding factors, such as other pro-inflammatory cytokines, including IL-6 and IL-8, in the progression of EOC. Future studies to address these limitations might help clarify these gaps. However, the studied parameters elucidate the possibility of using serum IL-16 levels as a biomarker in the screening of EOC patients.
Conclusion
From the data presented, this is the first investigation to determine IL-16 in serum as a possible clinical biomarker for assessing the progression of epithelial ovarian cancer. We are also the first group to propose the potential use of serum IL-16 as a prognostic marker for the survival of EOC patients.
Acknowledgements
The authors thank all the members of the various departments for their contribution during the research.
Footnotes
Disclosures: The authors declare that there are no conflicts of interest. No funding was received for this research. Approval for the study was obtained from the Institutional Review Committee of Ganzhou People’s Hospital. All the participants provided written informed consent as stipulated in the guideline of the approving committee.
- Received July 12, 2024.
- Revision received December 16, 2024.
- Accepted January 23, 2025.
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