The blockade of immune checkpoints in cancer immunotherapy.
The blockade of immune checkpoints in cancer immunotherapy.
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DOI：
10.1038/nrc3239
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发表时间：
2012-03-22
期刊：
影响因子：
--
通讯作者：
Pardoll DM
中科院分区：
文献类型：
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作者：
Pardoll DM
激活治疗性抗肿瘤免疫的最有希望的方法之一是阻断免疫检查点。免疫检查点是指与免疫系统硬连线的过多抑制途径，其对于维持自身耐受性和调节外周组织中生理免疫应答的持续时间和幅度以最小化附带组织损伤至关重要。现在很明显，肿瘤选择某些免疫检查点途径作为免疫抵抗的主要机制，特别是针对对肿瘤抗原具有特异性的T细胞。由于许多免疫检查点是由配体-受体相互作用引发的，因此它们可以容易地被抗体阻断或被重组形式的配体或受体调节。细胞毒性T淋巴细胞相关抗原4（CTLA 4）抗体是这类免疫治疗药物中第一个获得美国食品和药物管理局（FDA）批准的。其他免疫检查点蛋白（如程序性细胞死亡蛋白1（PD 1））阻断剂的初步临床研究结果表明，有广泛而多样的机会增强抗肿瘤免疫力，并有可能产生持久的临床反应。
Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand–receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.