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. 2024 Jun 14;16(12):2226.
doi: 10.3390/cancers16122226.

Plasmatic Inactive IL-18 Predicts a Worse Overall Survival for Advanced Non-Small-Cell Lung Cancer with Early Metabolic Progression after Immunotherapy Initiation

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Plasmatic Inactive IL-18 Predicts a Worse Overall Survival for Advanced Non-Small-Cell Lung Cancer with Early Metabolic Progression after Immunotherapy Initiation

Serena Janho Dit Hreich et al. Cancers (Basel). .

Abstract

The aim of this study was to assess the potential value of circulating active and inactive IL-18 levels in distinguishing pseudo and true tumor progression among NSCLC patients receiving immune checkpoint inhibitor treatments (ICIs).

Methods: This ancillary study includes 195 patients with metastatic non-small-cell lung cancer (NSCLC) treated with ICI in monotherapy, either pembrolizumab or nivolumab. Plasmatic levels of IL-18-related compounds, comprising the inhibitor IL-18 binding protein (IL-18BP), the inactive IL-18 (corresponding to IL-18/IL-18BP complex), and the active free IL-18, were assayed by ELISA. Objective tumoral response was analyzed by 18FDG PET-CT at baseline, 7 weeks, and 3 months post treatment induction, using PERCIST criteria.

Results: Plasmatic IL-18BP and total IL-18 levels are increased at baseline in NSCLC patients compared with healthy controls, whereas IL-18/IL-18BP complexes are decreased, and free IL-18 levels remain unchanged. Neither of the IL-18-related compounds allowed to discriminate ICI responding to nonresponding patients. However, inactive IL-18 levels allowed to discriminate patients with a first tumor progression, assessed after 7 weeks of treatment, with worse overall survival. In addition, we showed that neutrophil concentration is also a predictive indicator of patients' outcomes with OS (HR = 2.6, p = 0.0001) and PFS (HR = 2.2, p = 0.001).

Conclusions: Plasmatic levels of inactive IL-18, combined with circulating neutrophil concentrations, can effectively distinguish ICI nonresponding patients with better overall survival (OS), potentially guiding rapid decisions for therapeutic intensification.

Keywords: IL-18 signaling pathways; immune checkpoint inhibitor; lung adenocarcinoma; neutrophils.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The concentration of IL-18-related compounds in NSCLC patients: (a) Mature free IL-18 binds with a high affinity to IL-18 binding protein (IL-18BP) to form an inactive IL-18/IL-18BP complex. It also binds to the IL-18 receptor, composed of IL-18R1 and IL-18RAP, to activate NF-kB, which in turn controls the production of IFN-γ. Finally, IFN-γ induces a negative feedback loop through the production of IL-18BP. (b) The concentrations of free IL-18 and IL-18/IL-18BP complex were measured in plasma samples before ICI treatment. The amount of biologically active, free IL-18 from patients and controls was calculated as described in the Materials and Methods Section. Bars show median levels. Each point represents one sample. p-values were determined by the Wilcoxon rank sum test with continuity correction.
Figure 2
Figure 2
Free IL-18 concentration is decreased in ICI-treated patients: (a). Paired analysis of IL-18/IL-18BP complex and free IL-18 concentration at baseline, TEP1 and TEP2 from 123 individuals. p-values shown in supplementary Table S2 were determined by Wilcoxon test. Bars show median levels. Each point represents one sample. (b) Patients were divided into pseudoprogressors (light blue) or progressors (light pink) based on the TEP analysis, and IL-18 evolution between baseline and TEP1 was expressed as the percent of IL-18 at TEP1 relative to baseline. Pseudoprogressor n = 34, progressor n = 30. Bars show median levels. Each point represents one sample. p-values were determined by Mann–Whitney test.
Figure 3
Figure 3
Overall survival is increased in ICI nonresponding patients with low free IL-18. Survival analyses (Kaplan–Meier) of NSCLC patients showing all patients (left) and ICI nonresponding patients (right): (a) Free IL-18 and (b) IL-18/IL-18 complex. Blue lines correspond to concentrations lower than the cutoff. Red lines correspond to concentrations higher than the cutoff. Numbers at risk with censored data are shown. p-values were determined by Mentel–Cox test. HR: hazard ratio; IC: interval confidence.
Figure 4
Figure 4
Overall survival is increased in ICI nonresponding patients with low neutrophil concentration. Survival analyses (Kaplan–Meier): (a) Overall survival and (b) progression-free survival. Blue lines correspond to concentrations lower than the cutoff. Red lines correspond to concentrations higher than the cutoff. Numbers at risk with censored data are shown. p-values were determined by Mentel–Cox test. HR: hazard ratio; IC: interval confidence.
Figure 5
Figure 5
Overall survival of patients with combined prognostic factors. Survival analyses (Kaplan–Meier): (a) All patients and (b) nonresponding patients. Green lines correspond to patients with low risk (3 selected variables are lower than the cutoff) and red lines correspond to high risk (3 selected variables are higher than the cutoff). Numbers at risk with censored data are shown. p-values were determined by Mentel–Cox test.

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