Research ArticleExperimental Studies
Open Access

Elevated Plasma Interleukin-18 Levels in Head and Neck Squamous Cell Carcinoma: Correlation With IL-18 Binding Protein But Not Ferritin

JONAS FLECKNER, CHRISTIAN IDEL, ANKE LEICHTLE, ARMIN STEFFEN, KIRSTIN PLÖTZE-MARTIN, DIRK RADES, MARIE-NICOLE THEODORAKI, THOMAS K. HOFFMANN, KARL-LUDWIG BRUCHHAGE and RALPH PRIES
Anticancer Research March 2025, 45 (3) 943-954; DOI: https://doi.org/10.21873/anticanres.17482

Abstract

Background/Aim: Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy of the upper aerodigestive tract, associated with poor survival. As part of the HNSCC microenvironment, the interleukin-18 (IL-18)/IL-18 binding protein (IL-18BP) signaling is becoming increasingly interesting as a potential biomarker and therapeutic target. However, the systemic expression levels of IL-18BP in the context of the immunological environment in HNSCC patients remain unexplored.

Materials and Methods: ELISA measurements of plasma IL-18-BP were carried out with regard to associated inflammatory markers such as C-reactive protein, acute phase protein ferritin, and IL-18 in 34 patients with HNSCC before and during the course of radio(chemo)therapeutic treatment and in correlation to the clinicopathological parameters.

Results: Plasma IL-18BP concentrations were significantly elevated in HNSCC patients compared to healthy controls and correlated strongly with IL-18 levels before and after treatment. However, plasma ferritin levels, which were also elevated, showed no correlation with IL-18 or IL-18BP. Notably, changes in IL-18BP and IL-18 levels following therapy exhibited a well-maintained balance, indicating a functional feedback mechanism.

Conclusion: The results demonstrate a robust IL-18/IL-18BP feedback regulation in HNSCC, which likely aids tumor cells in evading anti-tumor immune responses. This balance, unaffected by radiotherapy or chemoradiotherapy, underscores the potential of IL-18BP as a therapeutic target and a prognostic biomarker in HNSCC.

Keywords:

Introduction

Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy originating in the upper aerodigestive tract (1, 2). Advanced stages of HNSCC are associated with poor prognosis and require innovative treatment approaches such as immune checkpoint inhibitors (ICIs) in order to prevent T-cell anergy (3-5). The reliability of available molecular markers for therapy decision making such as tumor type, tumor stage tissue expression levels of checkpoint molecule PD-L1 is still controversially discussed (6-10). Furthermore, a huge variety of different cytokines and growth factors of the HNSCC microenvironment is closely associated with HNSCC immune evasion and progression (11-13).

In this context, interleukin-18 (IL-18) signaling could be a promising biomarker and target as part of HNSCC treatment. IL-18 is a myeloid leukocyte inflammatory mediator whose main known function is to elicit interferon-γ (IFNγ) secretion from T and NK cells (14, 15). IL-18 acts in synergy with IL-12 to sustain the Th-1 immune response and to stimulate the secretion of further key pro-inflammatory cytokines such as IL-1 and TNF-α (16, 17).

Systemic administration of IL-18 significantly suppressed the proliferation of several carcinomas by stimulating immune cells such as monocytes, NK cells, and T cells, as well as promoting the production of IFNγ (18-20). However, the effect of IL-18 on cancer progression is complex and partly contradictory, since elevated serum levels of free IL-18 have also been correlated with poor survival rates in patients with pancreatic carcinoma (21). An earlier publication reported elevated serum levels of IL-18 in the majority of patients with HNSCC, suggesting its potential as a liquid biomarker for HNSCC (22).

In view of these controversial IL-18 related observations, the role of its natural inhibitor, IL-18-binding protein (IL-18BP), is becoming increasingly important. Soluble receptor protein IL-18BP is induced by IFNγ and thus acts as a negative feedback regulator of IL-18 bioactivity in the extracellular microenvironment (23). Of note, significantly increased IL-18BP serum concentrations have been observed after radiation exposure in mice, which suggests a possible connection with the treatment response and corroborates the complex underlying regulatory network (24). IL-18BP binds to IL-18 with a high affinity and thereby blocks the interaction of IL-18 with the IL-18Rα ligand-binding chain on the cell surface and the associated IL-18 signaling pathway (25). Major sources of IL-18BP secretion are mononuclear leukocytes such as monocytes and macrophages (26), but it can also be produced by endothelial cells and tumor cells (27, 28). In addition, it has been shown in patients with hemophagocytic syndrome (HPS) that a severe IL-18/IL-18BP imbalance with highly increased serum IL-18 levels results in an uncontrolled Th-1 lymphocyte and macrophage activation and hyper-inflammation (29). However, IL-18BP expression has been mostly investigated in vitro in different cell types and cell lines, but only poorly described in vivo so far (30).

The levels of systemic IL-18-binding protein in relation to the individual immunological status of patients with HNSCC have not yet been investigated. Therefore, we performed comprehensive measurements of plasma IL-18-BP concentrations and associated inflammatory markers in patients with HNSCC before and during the course of radio(chemo)therapeutic treatment, also in correlation with the individual disease progression and therapy response.

This study aimed to broaden the understanding of the IL-18/IL-18BP signaling as a systemic immune regulator and its potential role as a prognostic biomarker in patients with head and neck cancer.

Materials and Methods

Ethics statement and clinicopathological data. Patients were examined at the Department of Otorhinolaryngology, University Hospital Schleswig-Holstein, Campus Luebeck. The study was performed after written informed consent and approval of the ethics committee of the University of Luebeck (approval number 16-278). Blood samples were taken from healthy donors (n=11; mean age of 59) and patients with HNSCC (n=34; mean age of 67). Clinical parameters are shown in Table I.

View this table:
Table I.

Clinicopathological parameters.

Blood samples and cytokine analyses. Blood samples were taken into sodium citrate containing S-Monovettes (Sarstedt; Nümbrecht, Germany). Plasma samples were obtained by centrifugation at 1,000 × g for 10 min and stored at −80°C for subsequent investigations. Cytokines were analyzed using enzyme-linked immunosorbent assays (ELISA) (R&D Systems, Minneapolis, MN, USA).

Statistical analyses. GraphPad Prism Version 7.0f (GraphPad Software, Inc., San Diego, CA, USA) was used for statistical analyses and pairwise comparison of data was performed using student’s t-test. Correlations were calculated using multivariate regression with the Pearson correlation coefficient. p<0.05 (*), p<0.01 (**), and p<0.001 (***).

Results

Plasma IL-18BP concentrations in patients with HNSCC. Treatment naïve patients with primary HNSCC were included in our study and plasma IL-18BP levels were measured using commercially quantitative ELISA. Data revealed significantly increased plasma IL-18BP concentrations in patients with HNSCC (n=34) compared to healthy donors (HD, n=11) (Figure 1A). Measured IL-18BP levels were further considered in view of the standard clinicopathological features HPV-status (human papillomavirus) and tumor stage (TNM), but data revealed no significant differences (Figure 1B). Other parameters such as age, sex, and tumor type also revealed no correlation with the individual IL-18BP plasma concentration (data not shown). Initially, 34 patients with HNSCC were examined before radio(chemo)therapeutic (RCT) treatment. Of these, only 21 patients received about 12 months of RCT treatment, whilst five patients died during the course of therapy and eight patients discontinued RCT treatment. Our measurements revealed no significant differences of plasma IL-18BP concentrations among these patient subsets (no therapy vs. therapy) (Figure 2A). Furthermore, initial plasma IL-18BP levels of therapy receiving patients with HNSCC were compared to after RCT situation. Data revealed no overall significant differences between these two groups but strongly different individual shifts of plasma IL-18BP concentrations upon RCT treatment (Figure 2B).

Figure 1.
Figure 1.

Plasma interleukin-18 binding protein (IL-18BP) concentrations. (A) ELISA measurements revealed significantly increased plasma IL-18BP levels in patients with head and neck squamous cell carcinoma (HNSCC) (n=34) compared to healthy donors (HD, n=11). (B) Plasma IL-18BP levels of HPV positive vs. HPV negative patients with HNSCC and (C) TNM1/2 vs. TNM3/4 revealed no significant differences in our HNSCC cohort. ns: Not significant; ***p<0.001.

Figure 2.
Figure 2.

Plasma interleukin-18 binding protein (IL-18BP) in patients with head and neck squamous cell carcinoma (HNSCC) upon radio(chemo)therapy (RCT) treatment. (A) ELISA measurements revealed no significant differences between therapy receiving (n=21) and non-therapy receiving (n=13) patients with HNSCC, both of which revealed significantly increased IL-18BP levels compared to healthy donors (HD, n=11). (B) Plasma IL-18BP measurements revealed no overall significant differences between the pre and post RCT situation of patients with HNSCC, but strongly different individual IL-18BP shifts upon RCT treatment. ns: Not significant; **p<0.01; ***p<0.001.

Furthermore, clinical biomarkers of inflammation such as leukocyte count values, platelet count values and C-reactive protein (CRP) values were correlated with the measured plasma IL-18BP concentrations, whereas data revealed no significant correlations (Figure 3).

Figure 3.
Figure 3.

Correlation between plasma interleukin-18 binding protein (IL-18BP) concentrations and clinical blood values. Correlation analysis revealed no significant correlation between plasma IL-18BP and (A) leucocyte counts (×109/l), (B) platelet counts (×109/l), and (C) CRP levels (C-reactive protein; μg/ml). The correlation coefficient (r) and p-values are given for each correlation. p<0.05 was considered as significant.

To further assess the potential influence of circulating IL-18BP in the clinical setting of our HNSCC cohort, plasma concentrations of acute phase protein (APP) ferritin were analyzed, which is known to be associated with the IL-18 signaling pathway (31, 32). Data revealed significantly increased plasma ferritin levels in patients with HNSCC before RCT treatment compared to healthy donors, but no significant differences between the pre and post RCT situation (Figure 4A).

Figure 4.
Figure 4.

Increased levels of acute phase protein ferritin in patients with head and neck squamous cell carcinoma (HNSCC). (A) ELISA measurements revealed significantly increased plasma concentrations of acute phase protein ferritin (ng/ml) in patients with HNSCC (n=34) compared to healthy donors (HD, n=11), but no significant differences before (pre RCT) and after (post RCT) tween radio(chemo)therapy (RCT) treatment. (B) Correlation analysis between plasma interleukin-18 binding protein (IL-18BP) (ng/ml) and plasma ferritin (ng/ml) levels in patients with HNSCC revealed no significant correlations before and after RCT treatment. The correlation coefficient (r) and p-values are given for each correlation. p<0.05 was considered as significant. **p<0.01.

Correlation analysis between plasma IL-18BP and plasma ferritin levels in patients with HNSCC before and after radio(chemo)therapeutic treatment revealed no significant correlation (Figure 4B).

It is well known that an imbalanced IL-18/IL-18BP relation is associated with dysregulated immune responses. Therefore, plasma IL-18 concentrations of our HNSCC cohort were measured before and after radio(chemo)therapeutic treatment and compared to the corresponding IL-18BP values (Figure 5).

Figure 5.
Figure 5.
Figure 5.

Increased plasma interleukin-18 binding protein (IL-18BP) concentrations in patients with head and neck squamous cell carcinoma (HNSCC) significantly correlate with IL-18BP before (pre RCT) and after (post RCT) radio(chemo)therapy (RCT) treatment. (A) ELISA measurements revealed significantly increased plasma IL-18 levels in patients with HNSCC (n=34) compared to healthy individuals (HD, n=11). (B) Data revealed no significant differences between pre RCT and post RCT plasma IL-18 levels. (C) Correlation analysis between plasma IL-18 (pg/ml) and plasma ferritin (ng/ml) levels in patients with HNSCC revealed no significant correlations. (D) Correlation analysis between plasma IL-18BP (ng/ml) and plasma IL-18 (pg/ml) levels in patients with HNSCC revealed significant correlations before as well as after RCT treatment. The correlation coefficient (r) and p-values are given for each correlation. p<0.05 was considered as significant. ns: Not significant; *p<0.05.

ELISA measurements revealed significantly increased plasma IL-18 levels in patients with HNSCC compared to healthy donors, but no significant differences with regard to RCT treatment (Figure 4A and B). Of note, data revealed significant correlations between plasma IL-18BP and plasma IL-18 levels before as well as after RCT and thus indicate a well-balanced IL-18BP/IL-18 feedback regulatory system in patients with HNSCC, which gets not disturbed by RCT treatment.

Discussion

The HNSCC microenvironment consists of a complex mixture of innumerable different cytokines and growth factors, some of which contribute to pro- and/or anti-tumor immune responses depending upon the concentration, site of action and the underlying regulation (11-13). In this context, the balance of circulating IL-18 and its natural inhibitor IL-18-binding protein (IL-18BP) has not yet been investigated in patients with HNSCC. IL-18 belongs to the IL-1 cytokine family and mediates inflammation via MYD88 signaling and stimulation of T lymphocytes (33). Increased concentrations of systemic IL-18 in relation to its negative regulator IL-18BP are associated with numerous auto-inflammatory diseases due to a dysregulated immune response (25).

In view of its therapeutic potential, IL-18 has been reported to synergize with anti-tumor immune checkpoint inhibitors (ICIs) in mouse (34, 35), whereas other investigations revealed tumor-promoting effects of IL-18 (36-39). However, these findings do not necessarily contradict each other, but rather underline the pleiotropic effects of IL-18 in interaction with IL-18BP, which has been suggested to be a secreted barrier to IL-18 immunotherapy (40).

Our data revealed significantly increased plasma IL-18BP levels in patients with HNSCC compared to healthy donors, which revealed no significant differences with regard to different standard clinicopathological features such as HPV-status (human papillomavirus), age, tumor type or tumor stage (TNM). Furthermore, there was no significant correlation between the individual plasma IL-18BP levels and other clinical biomarkers of inflammation such as leukocyte count values, platelet count values and acute phase protein (APP) C-reactive protein (CRP), although IL-18/IL-18BP signaling has been implicated in APP release (31).

Another plasma marker in clinical practice is the APP ferritin, which acts as an intracellular iron storage protein and furthermore extracellular ferritin is known to have different immune regulatory influences (32). Ferritin has been shown to attenuate lymphocyte myelopoiesis and also induces the secretion of immunosuppressive IL-10 by regulatory T-lymphocytes (41, 42). Furthermore, elevated serum ferritin levels have been suggested as a potential serum marker for lymph node metastasis in HNSCC (43). Our measurements also revealed significantly increased plasma ferritin concentrations in patients with HNSCC compared to healthy donors, but no significant correlation neither with IL-18 nor with IL-18BP.

However, ELISA measurements showed significantly increased plasma IL-18 levels in patients with HNSCC, which positively correlated with the corresponding plasma concentrations of IL-18 binding protein before and after RCT treatment.

These data underline a well-balanced IL-18/IL-18BP feedback regulation in patients with HNSCC, which allows the tumor to limit an effective IL-18 anti-tumor immune stimulation, regardless of an applied RCT treatment. Recently, an anti-IL18BP blocker has been shown to unleash the pro-inflammatory activity of IL-18 and thus to stimulate a potent anti-tumor immune stimulation (44). In addition, different IL-18 constructs that do not bind IL-18BP have been developed to circumvent the strict regulation by the IL-18 binding protein (45).

Further investigations on larger patient cohorts over a longer period of time are required to better understand the relevance of the IL-18/IL-18BP regulation for tumor progression and for the clinical prognosis of patients with HNSCC. Taken together, our data suggest the plasma IL-18/IL18BP relation as a novel bioliquid marker and a promising target for an immunotherapeutic intervention in head and neck cancer.

Acknowledgements

The Authors are grateful to the participating patients and the involved members of our Departments for the good cooperation.

Footnotes

  • Authors’ Contributions

    JF, CI, KPM, and RP performed the molecular and statistical investigations and data curation. AL, AS, DR, MNT, TKH, KLB, and RP were significantly involved in the coordination of the study and writing of the manuscript. All Authors carefully read and approved the submitted manuscript and declare that there is no conflict of interest regarding the publication of this article.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Funding

    This study has been supported by a grant of the Walter-Schulz-Foundation to MNT and RP.

  • Received January 17, 2025.
  • Revision received January 28, 2025.
  • Accepted January 31, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Elevated Plasma Interleukin-18 Levels in Head and Neck Squamous Cell Carcinoma: Correlation With IL-18 Binding Protein But Not Ferritin
JONAS FLECKNER, CHRISTIAN IDEL, ANKE LEICHTLE, ARMIN STEFFEN, KIRSTIN PLÖTZE-MARTIN, DIRK RADES, MARIE-NICOLE THEODORAKI, THOMAS K. HOFFMANN, KARL-LUDWIG BRUCHHAGE, RALPH PRIES
Anticancer Research Mar 2025, 45 (3) 943-954; DOI: 10.21873/anticanres.17482
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