Buckle Irina, Guillerey Camille
Cancer Immunotherapies Laboratory, Mater Research Institute-The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD 4102, Australia.
Cancers (Basel). 2021 Aug 24;13(17):4263. doi: 10.3390/cancers13174263.
The discovery of immune checkpoints provided a breakthrough for cancer therapy. Immune checkpoints are inhibitory receptors that are up-regulated on chronically stimulated lymphocytes and have been shown to hinder immune responses to cancer. Monoclonal antibodies against the checkpoint molecules PD-1 and CTLA-4 have shown early clinical success against melanoma and are now approved to treat various cancers. Since then, the list of potential candidates for immune checkpoint blockade has dramatically increased. The current paradigm stipulates that immune checkpoint blockade therapy unleashes pre-existing T cell responses. However, there is accumulating evidence that some of these immune checkpoint molecules are also expressed on Natural Killer (NK) cells. In this review, we summarize our latest knowledge about targetable NK cell inhibitory receptors. We discuss the HLA-binding receptors KIRS and NKG2A, receptors binding to nectin and nectin-like molecules including TIGIT, CD96, and CD112R, and immune checkpoints commonly associated with T cells such as PD-1, TIM-3, and LAG-3. We also discuss newly discovered pathways such as IL-1R8 and often overlooked receptors such as CD161 and Siglecs. We detail how these inhibitory receptors might regulate NK cell responses to cancer, and, where relevant, we discuss their implications for therapeutic intervention.
免疫检查点的发现为癌症治疗带来了突破。免疫检查点是在长期受刺激的淋巴细胞上上调的抑制性受体，已被证明会阻碍对癌症的免疫反应。针对检查点分子PD-1和CTLA-4的单克隆抗体在黑色素瘤治疗中已显示出早期临床成效，目前已获批用于治疗多种癌症。自那时以来，免疫检查点阻断潜在候选药物的名单大幅增加。当前的模式规定，免疫检查点阻断疗法可释放预先存在的T细胞反应。然而，越来越多的证据表明，其中一些免疫检查点分子也在自然杀伤（NK）细胞上表达。在本综述中，我们总结了关于可靶向的NK细胞抑制性受体的最新知识。我们讨论了与HLA结合的受体KIRS和NKG2A、与nectin和nectin样分子结合的受体，包括TIGIT、CD96和CD112R，以及通常与T细胞相关的免疫检查点，如PD-1、TIM-3和LAG-3。我们还讨论了新发现的途径，如IL-1R8，以及经常被忽视的受体，如CD161和唾液酸结合免疫球蛋白样凝集素。我们详细阐述了这些抑制性受体如何调节NK细胞对癌症的反应，并在相关情况下讨论它们对治疗干预的意义。
