Tumour-intrinsic resistance to immune checkpoint blockade.
Tumour-intrinsic resistance to immune checkpoint blockade.
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DOI：
10.1038/s41577-019-0218-4
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发表时间：
2020-01
期刊：
影响因子：
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通讯作者：
Ribas A
中科院分区：
文献类型：
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作者：
Kalbasi A;Ribas A
针对癌症的“免疫检查点阻断”描述了治疗性抗体的使用，这种抗体扰乱了负面免疫调节检查点，并释放了原有的抗肿瘤免疫反应。针对检查点分子细胞毒性T淋巴细胞抗原4(CTLA4)、程序性细胞死亡1(PD1)和PD1配体1(PD-L1)的抗体已在临床上取得初步成功，这导致美国食品和药物管理局批准多种药物治疗几种癌症类型。然而，临床医生仍然没有非常有限的工具来区分对治疗有反应和没有反应的先验患者。这推动了对免疫检查点阻断的肿瘤固有抵抗的分子机制的研究浪潮，导致对抗肿瘤免疫至关重要的生物学过程的重新发现，即干扰素信号和抗原递呈。其他努力也阐明了典型的癌症信号通路的免疫学意义，如Wnt-β-连环蛋白信号通路、细胞周期调节信号通路、丝裂原激活的蛋白激酶信号通路以及肿瘤抑制因子磷酸肌醇磷脂酶PTEN缺失所激活的通路。在这里，我们回顾这些耐药的分子机制，并探索正在进行的克服免疫检查点阻断耐药性的方法，并扩大可从免疫检查点阻断受益的患者的范围。
‘Immune checkpoint blockade’ for cancer describes the use of therapeutic antibodies that disrupt negative immune regulatory checkpoints and unleash pre-existing antitumour immune responses. Antibodies targeting the checkpoint molecules cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1) and PD1 ligand 1 (PD-L1) have had early success in the clinic, which has led to approval by the US Food and Drug Administration of multiple agents in several cancer types. Yet, clinicians still have very limited tools to discriminate a priori patients who will and will not respond to treatment. This has fuelled a wave of research into the molecular mechanisms of tumour-intrinsic resistance to immune checkpoint blockade, leading to the rediscovery of biological processes critical to antitumour immunity, namely interferon signalling and antigen presentation. Other efforts have shed light on the immunological implications of canonical cancer signalling pathways, such as WNT–β-catenin signalling, cell cycle regulatory signalling, mitogen-activated protein kinase signalling and pathways activated by loss of the tumour suppressor phosphoinositide phosphatase PTEN. Here we review each of these molecular mechanisms of resistance and explore ongoing approaches to overcome resistance to immune checkpoint blockade and expand the spectrum of patients who can benefit from immune checkpoint blockade.