Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Lymphoid Cells of Innate Immunity Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Front Immunol. 2023 Aug 10;14:1229341. doi: 10.3389/fimmu.2023.1229341. eCollection 2023.
NK cells represent important effectors that play a major role in innate defences against pathogens and display potent cytolytic activity against tumor cells. An array of surface receptors finely regulate their function and inhibitory checkpoints, such as PD-1, can dampen the immune response inducing an immunosuppressive state. Indeed, PD-1 expression in human NK cells correlated with impaired effector function and tumor immune evasion. Importantly, blockade of the PD-1/PD-L1 axis has been shown to reverse NK cell exhaustion and increase their cytotoxicity. Recently, soluble counterparts of checkpoint receptors, such as soluble PD-1 (sPD-1), are rising high interest due to their biological activity and ability to modulate immune responses. It has been widely demonstrated that sPD-1 can modulate T cell effector functions and tumor growth. Tumor-infiltrating T cells are considered the main source of circulating sPD-1. In addition, recently, also stimulated macrophages have been demonstrated to release sPD-1. However, no data are present on the role of sPD-1 in the context of other innate immune cell subsets and therefore this study is aimed to unveil the effect of sPD-1 on human NK cell function. We produced the recombinant sPD-1 protein and demonstrated that it binds PD-L1 and that its presence results in increased NK cell cytotoxicity. Notably, we also identified a pathway regulating endogenous sPD-1 synthesis and release in human NK cells. Secreted endogenous sPD-1, retained its biological function and could modulate NK cell effector function. Overall, these data reveal a pivotal role of sPD-1 in regulating NK-mediated innate immune responses.
自然杀伤 (NK) 细胞是先天防御病原体的重要效应细胞，对肿瘤细胞具有强大的细胞毒性活性。一系列表面受体精细调节其功能，而抑制性检查点（如 PD-1）可以抑制免疫反应，诱导免疫抑制状态。事实上，人 NK 细胞中 PD-1 的表达与效应功能受损和肿瘤免疫逃逸有关。重要的是，阻断 PD-1/PD-L1 轴已被证明可以逆转 NK 细胞耗竭并增加其细胞毒性。最近，检查点受体的可溶性对应物，如可溶性 PD-1（sPD-1），由于其生物学活性和调节免疫反应的能力而引起了广泛关注。已经广泛证明 sPD-1 可以调节 T 细胞效应功能和肿瘤生长。肿瘤浸润 T 细胞被认为是循环 sPD-1 的主要来源。此外，最近还证明了受刺激的巨噬细胞也可以释放 sPD-1。然而，目前尚无关于 sPD-1 在其他先天免疫细胞亚群中的作用的数据，因此本研究旨在揭示 sPD-1 在人类 NK 细胞功能中的作用。我们产生了重组 sPD-1 蛋白，并证明它可以结合 PD-L1，并且其存在导致 NK 细胞的细胞毒性增加。值得注意的是，我们还确定了调节人 NK 细胞中内源性 sPD-1 合成和释放的途径。分泌的内源性 sPD-1 保留了其生物学功能，并可以调节 NK 细胞的效应功能。总体而言，这些数据揭示了 sPD-1 在调节 NK 介导的先天免疫反应中的关键作用。
