免疫检查点抑制剂治疗恶性肿瘤所致免疫相关不良反应预测标志物的研究进展

Research progress on predictive markers of immunological adverse events induced by immune checkpoint inhibitors in the treatment of malignant tumors

目的 对免疫检查点抑制剂(ICIs)治疗恶性肿瘤所致免疫相关不良反应(irAEs)的预测标志物研究进行综述,进一步提升对irAEs早期识别和治疗的能力,优化ICIs的治疗效能。方法 以“immune checkpoint inhibitor, immunotherapy, tumor/cancer/oncology/neoplasm/carcinoma, adverse event/toxicity, biomarker”为英文关键词,以“免疫检查点抑制剂,免疫治疗,癌症/恶性肿瘤,不良反应/毒性,标志物”为中文关键词,检索PubMed、万方和中国知网数据库2018-01-01-2023-10-31相关文献。共检索到184篇相关文献。纳入标准:聚焦于ICIs所致irAEs预测的生物标志物相关文献。排除标准:综述文献和会议论文。根据纳入和排除标准最终纳入62篇文献。结果 irAEs涉及全身多个器官,常见的包括皮肤相关疾病和结肠炎,少见的包括肝炎、肺炎、心肌炎、内分泌系统、神经系统和风湿免疫系统疾病等。目前常用预测标志物各具优缺点,大部分预测标志物的特异性并不高,抗结核抗体和抗线粒体抗体可能有助于预测ICIs诱导的肝损伤,血清游离型CD163、C-X-C模体趋化因子配体5(CXCL5)和大疱性类天疱疮(BP)180 IgG水平可以较为有效的预测皮肤相关irAE的发生。白细胞介素17(IL-17)、中性粒细胞、嗜酸性粒细胞和白细胞水平升高等,能够预测ICIs引发的结肠炎发生。嗜酸性细胞计数>240/μL和相对嗜酸性细胞计数>3.2%与内分泌irAE的发病显著相关。外周血标志物、肠道菌群及新兴标志物,如免疫细胞、细胞因子和自身抗体等,目前临床相关证据罕见报道,但发展前景乐观,期待能与其他标志物共同预测irAEs的发生。结论 依靠单一的标志物很难精确预测特定irAEs的发生,未来应加强多学科间的交叉协作,开展更大规模、更深层次的研究,同时在临床实践中联合使用多项标志物可能会更有效地预测irAEs的发生,从而提高临床医师对ICIs相关严重不良反应早期识别和及时治疗的能力。

Objective To review studies on predictive biomarkers for immune-related adverse events(irAEs)caused by immune checkpoint inhibitors(ICIs)in the treatment of malignant tumors and enhance the ability of early identification and treatment of irAEs,thereby optimizing the therapeutic efficacy of ICIs.Methods Using"immune checkpoint inhibitor,for predicting irAEs caused by ICIs.Exclusion criteria included review articles and conference papers.Finally,62 articles were included based on the inclusion and exclusion criteria.Results irAEs involve multiple organs throughout the body,commonly including skin-related diseases and colitis,while less common ones include hepatitis,pneumonia,myocarditis,endocrine system,nervous system,and rheumatic immune system diseases.Currently,commonly used predictive markers have their own advantages and disadvantages,and the specificity of most predictive markers is not high.Antibodies against tuberculosis and anti-mitochondrial antibodies may help predict liver injury induced by ICIs,while serum levels of sCD163,CXCL5,and bullous pemphigoid(BP)180 IgG can effectively predict the occurrence of skin-related irAEs.Elevated levels of IL-17,neutrophils,eosinophils,and white blood cells can predict the occurrence of colitis induced by ICIs.Eosinophil counts>240/μL and relative eosinophil counts>3.2%are significantly associated with the incidence of endocrine irAEs.Peripheral blood markers,gut microbiota,and emerging markers such as immune cells,cytokines,and autoantibodies have rarely been reported in clinical settings,but they have a promising future and are expected to predict irAEs together with other markers.Conclusion Relying on a single biomarker is difficult to accurately predict the occurrence of specific irAEs.In the future,interdisciplinary collaboration should be strengthened for larger-scale,deeper research.Moreover,the combined use of multiple biomarkers in clinical practice may more effectively predict the occurrence of irAEs,thus improving clinicians'ability to early identify and timely treat serious adverse reactions related to ICIs.