School of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
J Immunother Cancer. 2021 Apr;9(4). doi: 10.1136/jitc-2020-002189.
T cell exhaustion compromises antitumor immunity, and a sustained elevation of co-inhibitory receptors is a hallmark of T cell exhaustion in solid tumors. Similarly, upregulation of co-inhibitory receptors has been reported in T cells in hematological cancers such as chronic lymphocytic leukemia (CLL). However, the role of CD160, a glycosylphosphatidylinositol-anchored protein, as one of these co-inhibitory receptors has been contradictory in T cell function. Therefore, we decided to elucidate how CD160 expression and/or co-expression with other co-inhibitory receptors influence T cell effector functions in patients with CLL.
We studied 56 patients with CLL and 25 age-matched and sex-matched healthy controls in this study. The expression of different co-inhibitory receptors was analyzed in T cells obtained from the peripheral blood or the bone marrow. Also, we quantified the properties of extracellular vesicles (EVs) in the plasma of patients with CLL versus healthy controls. Finally, we measured 29 different cytokines, chemokines or other biomarkers in the plasma specimens of patients with CLL and healthy controls.
We found that CD160 was the most upregulated co-inhibitory receptor in patients with CLL. Its expression was associated with an exhausted T cell phenotype. CD160CD8 T cells were highly antigen-experienced/effector T cells, while CD160CD4 T cells were more heterogeneous. In particular, we identified EVs as a source of CD160 in the plasma of patients with CLL that can be taken up by T cells. Moreover, we observed a dominantly proinflammatory cytokine profile in the plasma of patients with CLL. In particular, interleukin-16 (IL-16) was highly elevated and correlated with the advanced clinical stage (Rai). Furthermore, we observed that the incubation of T cells with IL-16 results in the upregulation of CD160.
Our study provides a novel insight into the influence of CD160 expression/co-expression with other co-inhibitory receptors in T cell effector functions in patients with CLL. Besides, IL-16-mediated upregulation of CD160 expression in T cells highlights the importance of IL-16/CD160 as potential immunotherapy targets in patients with CLL. Therefore, our findings propose a significant role for CD160 in T cell exhaustion in patients with CLL.
T 细胞耗竭会损害抗肿瘤免疫，而在实体肿瘤中，共抑制受体的持续升高是 T 细胞耗竭的标志。同样，在慢性淋巴细胞白血病（CLL）等血液癌症中，也有报道称 T 细胞上调了共抑制受体。然而，作为这些共抑制受体之一的糖基磷脂酰肌醇锚定蛋白 CD160 的作用在 T 细胞功能中一直存在争议。因此，我们决定阐明 CD160 的表达和/或与其他共抑制受体的共表达如何影响 CLL 患者的 T 细胞效应功能。
本研究纳入了 56 例 CLL 患者和 25 例年龄和性别匹配的健康对照者。从外周血或骨髓中获得 T 细胞，分析不同共抑制受体的表达。此外，我们还定量分析了 CLL 患者与健康对照者血浆中的细胞外囊泡（EVs）。最后，我们测量了 CLL 患者和健康对照者血浆标本中的 29 种不同细胞因子、趋化因子或其他生物标志物。
我们发现，CD160 是 CLL 患者中上调最明显的共抑制受体。其表达与耗尽的 T 细胞表型相关。CD160+CD8+T 细胞是高度抗原经验/效应 T 细胞，而 CD160+CD4+T 细胞则更为异质性。特别是，我们发现 EVs 是 CLL 患者血浆中 CD160 的来源，可以被 T 细胞摄取。此外，我们观察到 CLL 患者血浆中存在以促炎细胞因子为主的特征性谱。特别是，白细胞介素-16（IL-16）高度升高，并与晚期临床分期（Rai）相关。此外，我们观察到，IL-16 孵育 T 细胞会导致 CD160 的上调。
本研究提供了关于 CD160 表达/与其他共抑制受体共表达对 CLL 患者 T 细胞效应功能影响的新见解。此外，IL-16 介导的 T 细胞中 CD160 表达的上调突出了 IL-16/CD160 作为 CLL 患者潜在免疫治疗靶点的重要性。因此，我们的发现表明 CD160 在 CLL 患者的 T 细胞耗竭中发挥了重要作用。
