Institute for Infection and Immunity, St. George's University of London, London, United Kingdom.
Front Immunol. 2023 Jan 13;13:1065495. doi: 10.3389/fimmu.2022.1065495. eCollection 2022.
Vγ9Vδ2 T-cells are a subset of T-cells with a crucial role in immunosurveillance which can be activated and expanded by multiple means to stimulate effector responses. Little is known about the expression of checkpoint molecules on this cell population and whether the ligation of these molecules can regulate their activity. The aim of this study was to assess the expression of both activatory and inhibitory receptors on Vγ9Vδ2 T-cells to assess potential avenues of regulation to target with immunotherapy.
Expression of various activatory and inhibitory receptors was assessed on Vγ9Vδ2 T-cells by flow cytometry following activation and expansion using zoledronic acid (ZA) and Bacillus Calmette-Guérin (BCG). Expression of these markers and production of effector molecules was also examined following co-culture with various tumour cell targets. The effect of immune checkpoint blockade on Vγ9Vδ2 T-cells was also explored.
Vγ9Vδ2 T-cells expressed high levels of activatory markers both at baseline and following stimulation. Vγ9Vδ2 T-cells expressed variable levels of inhibitory checkpoint receptors with many being upregulated following stimulation. Expression of these markers is further modulated upon co-culture with tumour cells with changes reflecting activation and effector functions. Despite their high expression of inhibitory receptors when cultured with tumour cells expressing cognate ligands there was no effect on Vδ2+ T-cell cytotoxic capacity or cytokine production with immune checkpoint blockade.
Our work suggests the expression of checkpoint receptors present on Vγ9Vδ2 T-cells which may provide a mechanism with the potential to be utilised by tumour cells to subvert Vγ9Vδ2 T-cell cytotoxicity. This work suggests important candidates for blockade by ICI therapy in order to increase the successful use of Vγ9Vδ2 T-cells in immunotherapy.
Vγ9Vδ2 T 细胞是 T 细胞的一个亚群，在免疫监视中起着至关重要的作用，可通过多种方式激活和扩增，以刺激效应反应。人们对这种细胞群上检查点分子的表达知之甚少，也不知道这些分子的连接是否可以调节它们的活性。本研究旨在评估 Vγ9Vδ2 T 细胞上共刺激和共抑制受体的表达，以评估潜在的免疫治疗靶点。
用唑来膦酸（ZA）和卡介苗（BCG）激活和扩增后，通过流式细胞术评估 Vγ9Vδ2 T 细胞上各种共刺激和共抑制受体的表达。还检查了与各种肿瘤细胞靶标共培养后这些标记物的表达和效应分子的产生。还探讨了免疫检查点阻断对 Vγ9Vδ2 T 细胞的影响。
Vγ9Vδ2 T 细胞在基线和刺激后均表达高水平的共刺激标记物。Vγ9Vδ2 T 细胞表达可变水平的抑制性检查点受体，许多在刺激后上调。与肿瘤细胞共培养后，这些标记物的表达进一步调节，变化反映了激活和效应功能。尽管 Vγ9Vδ2 T 细胞与表达同源配体的肿瘤细胞共培养时表达抑制性受体，但免疫检查点阻断对 Vδ2+T 细胞的细胞毒性或细胞因子产生没有影响。
我们的工作表明，Vγ9Vδ2 T 细胞上表达的检查点受体可能为肿瘤细胞提供一种潜在的机制，使其能够破坏 Vγ9Vδ2 T 细胞的细胞毒性。这项工作为 ICI 治疗提供了重要的阻断候选物，以增加 Vγ9Vδ2 T 细胞在免疫治疗中的成功应用。
