Sanchez-Correa Beatriz, Valhondo Isabel, Hassouneh Fakhri, Lopez-Sejas Nelson, Pera Alejandra, Bergua Juan M, Arcos Maria Jose, Bañas Helena, Casas-Avilés Ignacio, Durán Esther, Alonso Corona, Solana Rafael, Tarazona Raquel
Immunology Unit, Department of Physiology, University of Extremadura, 10003 Cáceres, Spain.
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain.
Cancers (Basel). 2019 Jun 23;11(6):877. doi: 10.3390/cancers11060877.
Natural killer (NK) cells are lymphocytes of the innate immune response characterized by their role in the destruction of tumor cells. Activation of NK cells depend on a fine balance between activating and inhibitory signals mediated by different receptors. In recent years, a family of paired receptors that interact with ligands of the Nectin/Nectin-like (Necl) family has attracted great interest. Two of these ligands, Necl-5 (usually termed CD155 or PVR) and Nectin-2 (CD112), frequently expressed on different types of tumor cells, are recognized by a group of receptors expressed on T and NK cells that exert opposite functions after interacting with their ligands. These receptors include DNAM-1 (CD226), TIGIT, TACTILE (CD96) and the recently described PVRIG. Whereas activation through DNAM-1 after recognition of CD155 or CD112 enhances NK cell-mediated cytotoxicity against a wide range of tumor cells, TIGIT recognition of these ligands exerts an inhibitory effect on NK cells by diminishing IFN-γ production, as well as NK cell-mediated cytotoxicity. PVRIG has also been identified as an inhibitory receptor that recognizes CD112 but not CD155. However, little is known about the role of TACTILE as modulator of immune responses in humans. TACTILE control of tumor growth and metastases has been reported in murine models, and it has been suggested that it negatively regulates the anti-tumor functions mediated by DNAM-1. In NK cells from patients with solid cancer and leukemia, it has been observed a decreased expression of DNAM-1 that may shift the balance in favor to the inhibitory receptors TIGIT or PVRIG, further contributing to the diminished NK cell-mediated cytotoxic capacity observed in these patients. Analysis of DNAM-1, TIGIT, TACTILE and PVRIG on human NK cells from solid cancer or leukemia patients will clarify the role of these receptors in cancer surveillance. Overall, it can be speculated that in cancer patients the TIGIT/PVRIG pathways are upregulated and represent novel targets for checkpoint blockade immunotherapy.
自然杀伤（NK）细胞是先天性免疫反应中的淋巴细胞，其特点是在肿瘤细胞破坏中发挥作用。NK细胞的激活取决于由不同受体介导的激活信号和抑制信号之间的精确平衡。近年来，一类与Nectin/Nectin样（Necl）家族配体相互作用的配对受体家族引起了极大关注。这些配体中的两种，Necl-5（通常称为CD155或PVR）和Nectin-2（CD112），经常在不同类型的肿瘤细胞上表达，被T细胞和NK细胞上表达的一组受体识别，这些受体在与它们的配体相互作用后发挥相反的功能。这些受体包括DNAM-1（CD226）、TIGIT、TACTILE（CD96）和最近描述的PVRIG。识别CD155或CD112后通过DNAM-1激活可增强NK细胞介导的对多种肿瘤细胞的细胞毒性，而TIGIT对这些配体的识别通过减少IFN-γ产生以及NK细胞介导的细胞毒性对NK细胞发挥抑制作用。PVRIG也已被鉴定为识别CD112但不识别CD155的抑制性受体。然而，关于TACTILE作为人类免疫反应调节剂的作用知之甚少。在小鼠模型中已报道TACTILE对肿瘤生长和转移的控制，并且有人提出它对DNAM-1介导的抗肿瘤功能具有负调节作用。在实体癌和白血病患者的NK细胞中，已观察到DNAM-1表达降低，这可能会使平衡向有利于抑制性受体TIGIT或PVRIG的方向转变，进一步导致这些患者中观察到的NK细胞介导的细胞毒性能力降低。对实体癌或白血病患者的人NK细胞上的DNAM-1、TIGIT、TACTILE和PVRIG进行分析将阐明这些受体在癌症监测中的作用。总体而言，可以推测在癌症患者中TIGIT/PVRIG途径上调，并且是检查点阻断免疫疗法的新靶点。
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