程序性细胞死亡蛋白配体1在结直肠癌免疫治疗中的研究进展

近年来,抗程序性细胞死亡蛋白1(PD-1)药物在转移性结直肠癌患者错配修复缺陷治疗中的成功使得该疾病的免疫治疗得以重视。然而,失配修复缺陷的结直肠癌患者仅占结肠癌患者的一部分。目前的研究重点是将免疫治疗应用到疾病的早期阶段,包括辅助一线治疗,以及检测免疫检查点抑制剂治疗的敏感性。然而,哪些患者能够从该免疫治疗中获益仍是值得商榷的问题,因为这类药物具有自身免疫毒性。PD-1的配体之一程序性细胞死亡蛋白配体1(PD-L1)作为一种检测生物标记物,其检测可以通过免疫组化来实现。但其免疫组化的检测存在一些混杂因素,包括应用不同的检测抗体、不同的免疫组化临界值、肿瘤组织的采集准备方式不同、处理过程的不同、原发与继发的活检标本、肿瘤源性或诱导的PD-L1表达,以及肿瘤与免疫细胞的染色等。目前的结果表明,免疫组化检测肿瘤过表达PD-L1的患者在接受抗PD-L1治疗时临床效果更理想,而有些低表达的肿瘤也对该治疗有所缓解,这使PD-L1的分析中存在复杂性。阐明宿主免疫系统与肿瘤微环境的机制则能够更好地解释针对PD-L1药物是否让患者受益。

Research progress of programmed death ligand 1 in immunotherapy of colorectal carcinoma

The recent success of anti-programmed death 1 (PD1) drugs in treatment of metastatic colorectal cancer patients with mismatch repair deficiency generated overwhelming enthusiasm for immunotherapy in this condition. However, patients with mismatch repair deficient colorectal cancer account for a small proportion of the colorectal cancer population. Current research focuses on advancing immunotherapy to earlier stages of the disease including adjuvant and first-line metastatic settings, and on inducing sensitivity to immune checkpoint inhibitor therapy through a combinatorial approach. However, which patients can benefit from the immunotherapy is an issue needing to be addressed because of the autoimmune toxicity of these drugs. As a detection biomarker, the programmed death ligand 1 (PD-L1) that is one of the ligands for PD-1 can be detected by immunohistochemistry. However, there are some confounding factors in the immunohistochemical detection, such as the application of different detection antibodies, different immunohistochemical threshold values, different collection and preparation methods of tumor tissues, different processing protocols, primary and secondary biopsy specimens, tumor-derived or induced PD-L1 expression, and staining of tumor and immune cells. The current results indicate that patients with tumor overexpression of PD-L1 by immunohistochemistry have better clinical effect when receiving anti-PDL1 treatment, while some tumors with low expression also have remission for this treatment, which lead to the complexities in PD-L1 analysis. Elucidation of the mechanism of host immune system and tumor microenvironment can better explain whether or not the drugs targeting PD-L1 are beneficial for the patients.