抗PD-(L)1、抗CTLA-4免疫治疗标志物研究进展

The research progress of anti-PD-(L)1 and anti-CTLA-4 immunotherapy markers

免疫检查点抑制剂已经改变了包括肺癌、黑色素瘤等许多肿瘤的治疗情况,并且在一些难治性肿瘤中表现出持久的应答率,然而在部分接受治疗的患者中表现出无反应及严重免疫相关副作用。为了优化免疫疗法的使用,可能需要多种临床应答的预测性标志物。本研究回顾了几种潜在有效生物标志物的可用数据,通过免疫组化检测肿瘤细胞和免疫细胞中PD-L1的表达,提示其是一种临床疗效的良好预测标志物;且PD-L1表达阴性者经免疫治疗后仍可获益。PD-L1表达在肿瘤内是动态和异质性的:在原发性灶和转移灶之间或在穿刺标本和大体标本之间表达不一致。肿瘤突变负荷与新抗原的高比率可获得持久获益。外周血标志物也可作为潜在标志物,增加的绝对淋巴细胞计数(ALC)与疾病控制和生存显著相关。在这篇综述中,我们旨在讨论抗PD-(L)1与抗CTLA-4免疫治疗相关标志物研究现状,为临床运用提供指导,以便能够准确筛选出从这些治疗中获益更多的患者。

Immune checkpoint inhibitors have changed the treatment of many tumors,including lung cancer and melanoma,and have shown a sustained response in some refractory tumors.However,some of the patients who received treatment showed no response and severe immune-related side effects.In order to optimize the use of immunotherapy,multiple predictive markers of clinical response may be required.We review here the data available for several potentially effective biomarkers.Detecting the expression of PD-L1 in tumor cells and immune cells by immunohistochemistry is a good predictor of clinical efficacy.However some patients with negative PD-L1 expression can still benefit from immunotherapy,for the existence of different antibodies,different thresholds and different targets.Moreover,the expression of PD-L1 is dynamic and heterogeneous in tumor.It is not consistent between primary focus and metastasis,or between puncture specimen and gross specimen.The high ratio of mutation load to new antigen is also associated with improved response.Peripheral blood markers could also provide information that increased absolute lymphocyte counts were significantly associated with disease control and survival.In this review,we aim to discuss the current status of research on anti-PD-(L)1 and anti CTLA-4 immunotherapy,to provide guidance for clinical practice,so that more patients can benefit from these treatments.