Clinical significance of tumor-derived IL-1β and IL-18 in localized renal cell carcinoma: Associations with recurrence and survival

Abstract

Purpose

Interleukin-1β (IL-1β) and IL-18 are products of activated inflammasomes that play central roles in innate immunity and inflammation. This study was aimed to determine the effect of tumor-derived IL-1β and IL-18 on recurrence and survival of patients with localized clear cell renal cell carcinoma (ccRCC) following surgery.

Methods

We retrospectively enrolled 267 patients with localized ccRCC undergoing nephrectomy at a single center. Clinicopathologic features, recurrence-free survival (RFS), and overall survival (OS) were recorded. IL-1β and IL-18 levels were assessed by immunohistochemistry in tumor tissues. The Kaplan-Meier method was used to compare survival curves. Cox regression models were used to analyze the effect of prognostic factors on RFS and OS. Concordance index was calculated to assess predictive accuracy.

Results

Both high IL-1β and high IL-18 levels were associated with increased risk of recurrence (P<0.001 and P<0.001, respectively) and reduced survival (P<0.001 and P = 0.001, respectively). The combination of IL-1β and IL-18 expression (IL-1β/IL-18 signature) could further refine prognostic stratification. Multivariate analyses confirmed that IL-1β/IL-18 signature was an independent prognostic factor for RFS and OS (P = 0.005 and P = 0.044, respectively). The predictive accuracy of well-established prognostic models improved when the IL-1β/IL-18 signature was added. Notably, the improvement in prediction was mainly observed in patients with low-risk disease.

Conclusions

The combined high expression of IL-1β and IL-18 is an independent predictor for poor prognosis in patients with localized ccRCC, and the prognostic value is more pronounced in patients with low-risk disease.

Introduction

Renal cell carcinoma (RCC) accounts for 2% to 3% of all cancers. It can be cured surgically if detected at early stages. Nevertheless, approximately 30% of patients undergoing nephrectomy for localized RCC experience local recurrence or distant metastasis, usually leading to incurable disease [1]. The natural history of RCC is complex, and the outcomes for patients with similar pathologic features can be very diverse [2]. Currently, several prognostic models have been proposed to identify patients who are at a greater risk of disease progression after nephrectomy. Kattan et al. [3] integrated disease-related symptoms, histologic subtype, tumor size, and TNM stage into a nomogram to predict 5-year recurrence-free survival (RFS) . On the basis of data from Mayo Clinic, the stage, size, grade, and necrosis score were developed to predict cancer-specific survival in patients with clear cell RCC (ccRCC) only [4]. The University of California Integrated Staging System (UISS) incorporated TNM stage, Fuhrman grade, and Eastern Cooperative Oncology Group performance status (ECOG-PS) to predict overall survival (OS) in patients with RCC regardless of histologic subtype [5]. The Mayo group further developed a model distinct from the stage, size, grade, and necrosis score to predict RFS in patients with localized ccRCC, which is referred to as the Leibovich prognostic score [6]. The predictive accuracy of these models may be further improved by the incorporation of novel prognostic biomarkers [7].

The inflammasome is a multiprotein complex typically consisting of a NOD-like receptor, the adapter protein ASC, and the cysteine protease caspase-1 [8]. During malignant transformation, inflammasomes are postulated to become activated in response to endogenous danger signals arising from tumors, which include adenosine triphosphate, heat shock proteins, and overexpressed or mutated self-antigens [9], [10]. Inflammasome activation leads to the autocleavage of pro-caspase-1 and its subsequent activation, which in turn promotes the secretion of potent proinflammatory cytokines interleukin 1β (IL-1β) and IL-18, and a form of programmed cell death known as “pyroptosis” [8]. In the complex interplay between malignant cells and their microenvironment, inflammasomes play diverse and sometimes contrasting roles in cancer development and therapy [11]. For instance, inflammasomes may operate at the cell-autonomous level to eliminate malignant precursors through pyroptosis [11]. Conversely, many cancers have been directly linked to inflammasome-mediated sterile inflammation. The inhibition of inflammasomes or neutralization of their products IL-1β and IL-18 has profound effects on tumor initiation and progression [12]. Thus, understanding inflammasome pathways may provide insight into carcinogenesis and identify novel prognostic biomarkers and potential therapeutic targets.

In this study, we analyzed IL-1β and IL-18 levels by immunohistochemistry in ccRCC tumor tissues and their associations with clinicopathologic characteristics and patient outcome. We further assessed the prognostic significance of the combined analysis of IL-1β and IL-18 expression, and its ability to improve the predictive accuracy of well-established prognostic models such as the UISS and Leibovich scores.