Wang Yifan, Zhang Zhening, Xie Tong, Liu Yudong, Zhang Cheng, Li Hao, Feng Ruiling, Huang Bo, Liu Qinghong, Wang Naidi, Xing Xiaoyan, Han Yipeng, Li Xue, Wang Ruoyi, He Jing, Peng Zhi
Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis, Beijing, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
Front Immunol. 2025 May 29;16:1559275. doi: 10.3389/fimmu.2025.1559275. eCollection 2025.
Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are limited by immune-related adverse events (irAEs). This study aimed to assess peripheral T cell profiles to identify irAEs biomarkers and construct predictive models.
In our study, we enrolled and followed 51 gastrointestinal cancer patients receiving anti-PD-1/PD-L1 therapies, with 22 developed irAEs (AE) and 29 didn't (NAE). We examined their peripheral blood using Olink technology, RNA-seq, and flow cytometry to explore the immunological characteristics of their circulating environment before and after early stages of ICIs treatment.
Our study discovered after early stages of ICIs treatment, a stronger upregulation of T cell activation genes, particularly Tfh-associated genes, was observed in AE patients. Flow cytometry result confirmed that AE patients exhibited elevated CD4CXCR5ICOS cells (p<0.01), CD4CXCR5ICOS cells (p<0.05) and Th1/Th2 ratio (p<0.05) after early stages. At baseline, AE patients had higher levels of serum inflammatory proteins including IL-12β, IL-15RA and CXCL9 (p<0.05). Higher peripheral Tfh (p<0.05), Tph (p<0.001) were also observed in the baseline flow cytometry result of AE patients compared to NAE patients. Based on these findings, predictive models for both irAEs and grade 2-4 irAEs were established, demonstrating good discriminatory ability.
This study demonstrates that high-dimensional immune profiling can uncover novel blood-based immune signatures associated with the risk and mechanism of severe irAEs are effective biomarkers for predicting irAEs at both baseline and early stages of ICIs treatment.
免疫检查点抑制剂（ICI）已改变癌症治疗方式，但受免疫相关不良事件（irAE）限制。本研究旨在评估外周血T细胞谱，以识别irAE生物标志物并构建预测模型。
在本研究中，我们招募并随访了51例接受抗PD-1/PD-L1治疗的胃肠道癌患者，其中22例发生irAE（AE组），29例未发生（NAE组）。我们使用Olink技术、RNA测序和流式细胞术检测他们的外周血，以探索ICI治疗早期前后其循环环境的免疫特征。
我们的研究发现，在ICI治疗早期后，AE组患者中T细胞激活基因，特别是与滤泡辅助性T细胞（Tfh）相关的基因上调更为明显。流式细胞术结果证实，AE组患者在早期后CD4CXCR5ICOS细胞（p<0.01）、CD4CXCR5ICOS细胞（p<0.05）和Th1/Th2比值（p<0.05）升高。基线时，AE组患者的血清炎症蛋白水平较高，包括白细胞介素-12β（IL-12β）、白细胞介素-15受体α（IL-15RA）和CXC趋化因子配体9（CXCL9）（p<0.05）。与NAE组患者相比，AE组患者基线流式细胞术结果中还观察到更高的外周血Tfh（p<0.05）、Tph（p<0.001）。基于这些发现，建立了irAE和2-4级irAE的预测模型，显示出良好的区分能力。
本研究表明，高维免疫谱分析可以揭示与严重irAE风险和机制相关的新型血液免疫特征，是在ICI治疗基线和早期预测irAE的有效生物标志物。
