Farooqi Saima Jamil, Zhao Zhi, Öjlert Åsa Kristina, Thunold Solfrid, Juul Hedvig Vidarsdotter, Bjaanæs Maria Moksnes, Horndalsveen Henrik, Nymoen Hanne Marte Gjertsen, Helland Åslaug, Haakensen Vilde Drageset
Department of Oncology, Oslo University Hospital, Oslo, Norway.
Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway.
Front Immunol. 2024 Dec 2;15:1480183. doi: 10.3389/fimmu.2024.1480183. eCollection 2024.
Pleural mesothelioma (PM) is a rare cancer with a dismal prognosis. Dual immune checkpoint inhibitors have improved overall survival, but the rate of immune-related adverse events (irAEs) is high. Serum cytokines reflect systemic immune reactions and may serve as biomarkers for irAEs.
Patients with pleural mesothelioma treated with nivolumab and ipilimumab with or without UV1 vaccine in the NIPU study were included. Serum cytokine levels were measured by Bio-Plex Pro Human Cytokine Screening 48-Plex Panel Assay. Correlations between cytokine levels and irAEs were analyzed by generalized linear mixed models to identify potential diagnostic and predictive biomarkers.
Higher levels of MIG, eotaxin, MIP-1α, IP-10, TNF-α, MIP-1β, IL-4, MIF, IL-16, IL-2RA, SCGF.β and PDFG-BB at baseline are associated with increased risk of developing one or more irAEs. In particular, higher baseline levels of MIG are positively associated with thyroiditis and hypophysitis, and elevated levels of IP-10 and MIG to dermatitis. During the course of treatment, higher levels of MIG, eotaxin, MIF, TNF-α, MIP-1β, IL-4 and IL-16 are associated with an ongoing irAE. We found both predictive and diagnostic value of MIF with fatigue and of eotaxin with both colitis and pneumonitis. Higher levels of CTACK is associated with a lower risk of developing hepatitis, both before and after treatment.
Elevated levels of certain cytokines, both before and after onset of treatment, correlate with specific irAEs in PM patients receiving ICIs. These cytokines may be used as biomarkers to predict and detect irAES.
胸膜间皮瘤（PM）是一种预后较差的罕见癌症。双重免疫检查点抑制剂可改善总生存期，但免疫相关不良事件（irAE）的发生率较高。血清细胞因子反映全身免疫反应，可能作为irAE的生物标志物。
纳入NIPU研究中接受纳武单抗和伊匹单抗治疗（联合或不联合UV1疫苗）的胸膜间皮瘤患者。采用Bio-Plex Pro人细胞因子筛选48种细胞因子检测板测定血清细胞因子水平。通过广义线性混合模型分析细胞因子水平与irAE之间的相关性，以确定潜在的诊断和预测生物标志物。
基线时较高水平的MIG、嗜酸性粒细胞趋化因子、MIP-1α、IP-10、TNF-α、MIP-1β、IL-4、MIF、IL-16、IL-2RA、SCGF.β和PDFG-BB与发生一种或多种irAE的风险增加相关。特别是，较高的基线MIG水平与甲状腺炎和垂体炎呈正相关，而IP-10和MIG水平升高与皮炎相关。在治疗过程中，较高水平的MIG、嗜酸性粒细胞趋化因子、MIF、TNF-α、MIP-1β、IL-4和IL-16与持续的irAE相关。我们发现MIF对疲劳以及嗜酸性粒细胞趋化因子对结肠炎和肺炎均具有预测和诊断价值。治疗前后，较高水平的CTACK与发生肝炎的风险较低相关。
在接受免疫检查点抑制剂治疗的PM患者中，治疗前后某些细胞因子水平的升高与特定的irAE相关。这些细胞因子可作为预测和检测irAE的生物标志物。
