Nakahara Yoshiro, Kouro Taku, Motoyama Satoru, Miura Masatomo, Fujita Kazuma, Igarashi Yuka, Higashijima Naoko, Matsuo Norikazu, Himuro Hidetomo, Wei Feifei, Horaguchi Shun, Tsuji Kayoko, Mano Yasunobu, Komahashi Mitsuru, Saito Haruhiro, Azuma Koichi, Sasada Tetsuro
Department of Respiratory Medicine, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.
Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
Front Cell Dev Biol. 2024 Jan 16;11:1324898. doi: 10.3389/fcell.2023.1324898. eCollection 2023.
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. 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. 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, = 0.012) in NSCLC patients treated with ICIs. However, plasma sIL-6R and sgp130 levels showed no prognostic significance ( = 0.882 and = 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 ( = 0.647, = 0.727, and = 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 ( = 0.908 and = 0.639, respectively). 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.
血浆白细胞介素-6（IL-6）水平在接受免疫检查点抑制剂（ICI）治疗的包括非小细胞肺癌（NSCLC）在内的各种癌症患者中的临床作用已有报道。然而，血浆中其他IL-6信号成分，可溶性IL-6受体（sIL-6R）和可溶性糖蛋白130（sgp130）的作用尚未阐明。在106例NSCLC患者开始ICI治疗（抗PD-1或抗PD-L1抗体）前采集血液。通过Cox回归风险模型评估IL-6、sIL-6R、sgp130及其复合物的血浆水平，以评估其临床意义。还分析了IL-6或IL-6R基因多态性的临床作用。Cox回归分析显示，较高的血浆IL-6水平显著预测接受ICI治疗的NSCLC患者的总生存期（OS）不佳（风险比[HR]1.34，95%置信区间[CI]1.05-1.68，P=0.012）。然而，血浆sIL-6R和sgp130水平无预后意义（分别为P=0.882和P=0.934）。此外，二元IL-6:sIL-6R和三元IL-6:sIL-6R:sgp130复合物的估计浓度及其比率（二元/三元复合物）与OS无显著相关性（分别为P=0.647、P=0.727和P=0.273）。此外，通过Kaplan-Meier生存分析，IL-6（-634G>C）和IL-6R（48892A>C）的基因多态性无临床作用（分别为P=0.908和P=0.639）。这些发现证明了血浆IL-6水平的临床意义，但其他IL-6信号成分sIL-6R和sgp130则无此意义，提示经典IL-6信号而非转信号可能与接受ICI治疗的癌症患者的抗肿瘤免疫反应有关。
