Zhou Binghan, Gao Yuan, Zhang Peng, Chu Qian
Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Immunol. 2021 Jun 14;12:693609. doi: 10.3389/fimmu.2021.693609. eCollection 2021.
The immune checkpoint blockade therapy has completely transformed cancer treatment modalities because of its unprecedented and durable clinical responses in various cancers. With the increasing use of immune checkpoint blockades in clinical practice, a large number of patients develop acquired resistance. However, the knowledge about acquired resistance to immune checkpoint blockades is limited and poorly summarized. In this review, we clarify the principal elements of acquired resistance to immune checkpoint blockades. The definition of acquired resistance is heterogeneous among groups or societies, but the expert consensus of The Society for Immunotherapy of Cancer can be referred. Oligo-progression is the main pattern of acquired resistance. Acquired resistance can be derived from the selection of resistant cancer cell clones that exist in the tumor mass before therapeutic intervention or gradual acquisition in the sensitive cancer cells. Specifically, tumor intrinsic mechanisms include neoantigen depletion, defects in antigen presentation machinery, aberrations of interferon signaling, tumor-induced exclusion/immunosuppression, and tumor cell plasticity. Tumor extrinsic mechanisms include upregulation of other immune checkpoints. Presently, a set of treatment modalities is applied to patients with similar clinical characteristics or resistance mechanisms for overcoming acquired resistance, and hence, further research is required.
免疫检查点阻断疗法彻底改变了癌症治疗模式，因为它在各种癌症中产生了前所未有的持久临床反应。随着免疫检查点阻断剂在临床实践中的使用日益增加，大量患者出现了获得性耐药。然而，关于免疫检查点阻断剂获得性耐药的知识有限且总结不足。在这篇综述中，我们阐明了免疫检查点阻断剂获得性耐药的主要因素。获得性耐药的定义在不同群体或社会中存在异质性，但可参考癌症免疫治疗学会的专家共识。寡进展是获得性耐药的主要模式。获得性耐药可源于治疗干预前肿瘤块中存在的耐药癌细胞克隆的选择或敏感癌细胞中的逐渐获得。具体而言，肿瘤内在机制包括新抗原耗竭、抗原呈递机制缺陷、干扰素信号异常、肿瘤诱导的排斥/免疫抑制以及肿瘤细胞可塑性。肿瘤外在机制包括其他免疫检查点的上调。目前，针对具有相似临床特征或耐药机制的患者应用了一系列治疗模式来克服获得性耐药，因此，还需要进一步研究。
