Assessment of interferon-γ in pleural fluid as a prognostic factor of survival in malignant pleural mesothelioma

Abstract

Backgound: Literature reports suggest that the host immune system may control Malignant Pleural Mesothelioma (MPM) growth, although its activity is limited by regulatory mechanisms. In this retrospective study, we analyzed the levels of pro-inflammatory (IL-1, IL-6, TNF), immune-regulatory (IL-10) and Th1/CTL-related cytokines (IL-12p70, IFN-γ) in the pleural exudate and their relationship with overall survival (OS) in MPM.

Methods: Cytokines were quantified by multiplexed immunoassay. Concentrations were dichotomized with respect to the median value. Correlation between cytokine level and OS was assessed using univariate (Kaplan-Meier curves) and multivariate (Cox regression) analyses.

Results: Regarding outcome, tumor histology, therapies undergone and IFN-γ were independent prognostic factors of OS in a 72 MPM training cohort. Notably, high concentrations of IFN-γ halved death probability (HR of high vs low IFN-γ concentration = 0.491, 95%CI 0.3-0.8, p = 0.007). Also in patients with epithelioid histology and those receiving at least one line of therapy, high IFN-γ level was an independent factor predictive of OS (HR of high vs low IFN-γ concentration were 0.497, p = 0.007 and 0.324, p = 0.006, respectively). However, these data were not confirmed in a 77 MPM validation cohort, possibly due to the low IFN-γ levels encountered in this population, and the heterogeneous distribution of disease stages between the training and the validation cohorts. None of the other cytokines showed any effect on survival.

Conclusions: High level of IFN-γ in pleural effusion may be associated with better survival in MPM patients and potentially serve as a prognostic biomarker. Larger prospective studies are needed to ascertain this hypothesis.

Keywords: Biomarker; Immune response; Interferon-gamma; Mesothelioma; Outcome; Pleural effusion.

Fig. 1

Levels of each cytokine in pleural effusion. The concentrations, in pg/ml, of IFN-γ, IL-10, IL-12p70, IL-1, TNF and IL-6 in pleural effusions of MPM patients are shown. Both training a and validation cohorts b are displayed. Right panels show the ratio values of IL-10/IL-12, used to define regulatory macrophages. Bars indicate median values

Fig. 2

Kaplan–Meier survival curves according to IFN-γ concentration (as dichotomized around the median value of 13.8 pg/ml) in the whole population

Fig. 3

Kaplan–Meier survival curves according to IFN-γ concentration (as dichotomized around the median value of 13.8 pg/ml) in the subgroup of patients with epithelioid histotype a and the subgroup of patients undergoing at least one line of therapy b. The insets report the HR values for IFN-γ (as > 13.8 pg/ml vs ≤ 13.8 pg/ml) obtained in multivariate Cox regressions including in a gender, tumor stage, ECOG score, therapy undergone and IFN-γ concentration; in b gender, histology, tumor stage, ECOG score and IFN-γ concentration