Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors

Abstract

Introduction: Clinical roles of plasma IL-6 levels have been reported in patients with various cancers, including non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (ICIs). However, the roles of other IL-6 signaling components, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130), in the plasma have not been elucidated. Methods: Blood was collected from 106 patients with NSCLC before initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Plasma levels of IL-6, sIL-6R, sgp130, and their complexes were assessed by Cox regression hazard model to evaluate their clinical significance. The clinical role of IL-6 or IL-6R genetic polymorphisms was also analyzed. Results: Cox regression analysis showed that higher plasma IL-6 levels significantly predicted unfavorable overall survival (OS; hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.05-1.68, p = 0.012) in NSCLC patients treated with ICIs. However, plasma sIL-6R and sgp130 levels showed no prognostic significance (p = 0.882 and p = 0.934, respectively). In addition, the estimated concentrations of binary IL-6:sIL-6R and ternary IL-6:sIL-6R:sgp130 complexes and their ratios (binary/ternary complex) were not significantly associated with OS (p = 0.647, p = 0.727, and p = 0.273, respectively). Furthermore, the genetic polymorphisms of IL-6 (-634G>C) and IL-6R (48892A>C) showed no clinical role by Kaplan-Meier survival analysis (p = 0.908 and p = 0.639, respectively). Discussion: These findings demonstrated the clinical significance of plasma levels of IL-6, but not of other IL-6 signaling components, sIL-6R and sgp130, suggesting that classical IL-6 signaling, but not trans-signaling, may be related to anti-tumor immune responses in cancer patients treated with ICIs.

Keywords: IL-6; PD-1; PD-L1; immune checkpoint inhibitor; non-small cell lung cancer (NSCLC); soluble IL-6 receptor (sIL-6R); soluble glycoprotein 130 (sgp130).

FIGURE 1

Prognostic significance of plasma IL-6 levels in ICI-treated NSCLC patients. Patients treated with ICIs were divided into two groups based on the plasma IL-6 levels. The optimal cut-off value for OS (13.4 pg/mL) was determined using the Cutoff Finder web application. Curves for OS were estimated using the Kaplan-Meier method and statistically evaluated using the log-rank test (p = 0.029).

FIGURE 2

No prognostic significance of IL-6 (−634G>C) and IL-6R (48892A>C) genetic polymorphisms in NSCLC patients treated with ICIs. (A) Patients treated with ICIs were divided into three subgroups according to the IL-6 (−634G>C) polymorphism [IL-6 -634G/G (n = 4), C/G (n = 38), C/C (n = 64)]. Curves for OS were estimated by the Kaplan-Meier method and statistically evaluated by the log-rank test (p = 0.908). (B) Patients treated with ICIs were divided into three subgroups according to the IL-6R 48892A>C polymorphism [IL-6R 48892C/C (n = 19), A/C (n = 51), A/A (n = 36)]. Curves for OS were estimated by the Kaplan-Meier method and statistically evaluated by the log-rank test (p = 0.639).

FIGURE 3

Differences in plasma IL-6 and sIL-6R levels according to the IL-6 (−634G>C) or IL-6R (48892A>C) polymorphism. Plasma IL-6 and sIL-6R levels were compared among three subgroups according to the IL-6 (−634G>C) (A) or IL-6R (48892A>C) (B) polymorphism by Student’s t-test. Data are presented as box plots. The bottom and top of the box represent the first and third quartiles, and the band and “X” inside the box correspond to the median and mean, respectively. Whiskers indicate the variability outside the upper and lower quartiles. Outliers are shown as individual points. *p < 0.001. NS, not significant (p > 0.05).