文章：

肿瘤免疫治疗中免疫检查点的阻断

The blockade of immune checkpoints in cancer immunotherapy

原文发布日期：2012-03-22

DOI: 10.1038/nrc3239

类型: Review Article

开放获取: 否

要点：

1. The huge number of genetic and epigenetic changes that are inherent to most cancer cells provide plenty of tumour-associated antigens that the host immune system can recognize, thereby requiring tumours to develop specific immune resistance mechanisms. An important immune resistance mechanism involves immune-inhibitory pathways, termed immune checkpoints, which normally mediate immune tolerance and mitigate collateral tissue damage.
2. A particularly important immune-checkpoint receptor is cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), which downmodulates the amplitude of T cell activation. Antibody blockade of CTLA4 in mouse models of cancer induced antitumour immunity.
3. Clinical studies using antagonistic CTLA4 antibodies demonstrated activity in melanoma. Despite a high frequency of immune-related toxicity, this therapy enhanced survival in two randomized Phase III trials. Anti-CTLA4 therapy was the first agent to demonstrate a survival benefit in patients with advanced melanoma and was approved by the US Food and Drug Administration (FDA) in 2010.
4. Some immune-checkpoint receptors, such as programmed cell death protein 1 (PD1), limit T cell effector functions within tissues. By upregulating ligands for PD1, tumour cells block antitumour immune responses in the tumour microenvironment.
5. Early-stage clinical trials suggest that blockade of the PD1 pathway induces sustained tumour regression in various tumour types. Responses to PD1 blockade may correlate with the expression of PD1 ligands by tumour cells.
6. Multiple additional immune-checkpoint receptors and ligands, some of which are selectively upregulated in various types of tumour cells, are prime targets for blockade, particularly in combination with approaches that enhance the activation of antitumour immune responses, such as vaccines.

要点翻译：

1. 大多数癌细胞固有的遗传和表观遗传改变的巨大数量提供了大量宿主免疫系统可以识别的肿瘤相关抗原，从而要求肿瘤发展特定的免疫抵抗机制。一种重要的免疫抵抗机制涉及免疫抑制通路，称为免疫检查点，这些通路通常介导免疫耐受并减轻附带组织损伤。
2. 一个特别重要的免疫检查点受体是细胞毒性T淋巴细胞相关抗原4（CTLA4），它能下调T细胞激活的幅度。在癌症小鼠模型中，CTLA4的抗体阻断诱导了抗肿瘤免疫。
3. 使用拮抗性CTLA4抗体的临床研究在黑色素瘤中显示出活性。尽管存在高频率的免疫相关毒性，该疗法在两项随机III期试验中提高了生存率。抗CTLA4疗法是首个在晚期黑色素瘤患者中显示生存获益的药物，并于2010年获得美国食品药品监督管理局（FDA）批准。
4. 一些免疫检查点受体，如程序性细胞死亡蛋白1（PD1），限制组织内的T细胞效应功能。通过上调PD1的配体，肿瘤细胞在肿瘤微环境中阻断抗肿瘤免疫反应。
5. 早期临床试验表明，阻断PD1通路可在多种肿瘤类型中诱导持续的肿瘤消退。对PD1阻断的反应可能与肿瘤细胞表达PD1配体相关。
6. 许多额外的免疫检查点受体和配体，其中一些在各种类型的肿瘤细胞中选择性上调，是阻断的主要目标，特别是与增强抗肿瘤免疫反应激活的方法（如疫苗）结合使用时。

英文摘要：

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.

摘要翻译： 

激活治疗性抗肿瘤免疫最有前景的方法之一是阻断免疫检查点。免疫检查点是指免疫系统内固有的多种抑制性通路，它们对于维持自身耐受以及调节外周组织中生理免疫反应的持续时间与强度至关重要，旨在最大限度减少附带组织损伤。现已明确，肿瘤会“劫持”某些免疫检查点通路，作为其抵抗免疫的主要机制，尤其是针对识别肿瘤抗原的T细胞。由于众多免疫检查点通过配体-受体相互作用启动，它们可以被抗体轻易阻断，或通过重组配体或受体形式加以调节。细胞毒性T淋巴细胞相关抗原4（CTLA4）抗体是这类免疫治疗药物中首个获得美国食品药品监督管理局（FDA）批准的。针对其他免疫检查点蛋白（如程序性死亡蛋白1，PD1）阻断剂的初步临床结果显示，增强抗肿瘤免疫具有广泛而多样的机会，并有望带来持久的临床反应。

原文链接：

The blockade of immune checkpoints in cancer immunotherapy