Rezaeifar Maryam, Shahbaz Shima, Peters Anthea C, Gibson Spencer B, Elahi Shokrollah
Division of Foundational Sciences, Mike Petryk School of Dentistry, University of Alberta, Edmonton, Canada.
Division of Medical Oncology, Department of Oncology, University of Alberta, Edmonton, Canada.
Mol Oncol. 2025 May;19(5):1347-1370. doi: 10.1002/1878-0261.13793. Epub 2025 Jan 7.
CD8 T cells, a subset of T cells identified by the surface glycoprotein CD8, particularly those expressing the co-stimulatory molecule CD226, play a crucial role in the immune response to malignancies. However, their role in chronic lymphocytic leukemia (CLL), an immunosuppressive disease, has not yet been explored. We studied 64 CLL patients and 25 age- and sex-matched healthy controls (HCs). We analyzed the proportion of CD226-expressing cells among different CD8 T cell subsets (including naïve, central memory, effector memory, and effectors) in CLL patients, stratified by Rai stage and immunoglobulin heavy-chain variable region gene (IgHV) mutation status. Additionally, we compared the effector functions of CD8CD226 cells and their CD226 counterparts. We also quantified cytokine and chemokine levels in the plasma of CLL and HCs. Furthermore, we reanalyzed the publicly available bulk RNA-seq on CD226 and CD226CD8 T cells. Finally, we evaluated the impact of elevated cytokines/chemokines on CD226 expression. Our results showed that CD226-expressing cells were significantly decreased within the effector memory and effector CD8 T cell subsets in CLL patients with advanced Rai stages and unmutated IgHV, a marker of poor prognosis. These cells displayed robust effector functions, including cytokine production, cytolytic activity, degranulation, proliferation, and migration capacity. In contrast, CD8CD226 T cells displayed an exhausted phenotype with reduced Runt-related transcription factor 2 (RUNX2) expression. Elevated levels of interleukin-6 (IL-6) and macrophage inflammatory protein-1 beta (MIP-1β) were inversely correlated with the frequency of CD8CD226 T cells and may contribute to the downregulation of CD226, possibly leading to T cell dysfunction in CLL. Our findings highlight the critical role of CD8CD226RUNX2 T cells in CLL and suggest that their reduction is associated with disease progression and poor clinical outcomes. This study also underscores the potential of targeting IL-6 and MIP-1β to preserve polyfunctional CD8CD226 T cells as a promising immunotherapy strategy.
CD8 T细胞是通过表面糖蛋白CD8鉴定的T细胞亚群，尤其是那些表达共刺激分子CD226的细胞，在对恶性肿瘤的免疫反应中起关键作用。然而，它们在慢性淋巴细胞白血病（CLL）这种免疫抑制性疾病中的作用尚未得到探索。我们研究了64例CLL患者和25例年龄及性别匹配的健康对照（HCs）。我们分析了CLL患者中不同CD8 T细胞亚群（包括初始、中枢记忆、效应记忆和效应细胞）中表达CD226的细胞比例，并根据Rai分期和免疫球蛋白重链可变区基因（IgHV）突变状态进行分层。此外，我们比较了CD8CD226细胞及其CD226阴性对应细胞的效应功能。我们还对CLL患者和HCs血浆中的细胞因子和趋化因子水平进行了定量。此外，我们重新分析了公开可用的关于CD226和CD226阴性CD8 T细胞的批量RNA测序数据。最后，我们评估了细胞因子/趋化因子升高对CD226表达的影响。我们的结果表明，在Rai分期晚期且IgHV未突变（预后不良的标志物）的CLL患者中，效应记忆和效应CD8 T细胞亚群中表达CD226的细胞显著减少。这些细胞表现出强大的效应功能，包括细胞因子产生、溶细胞活性、脱颗粒、增殖和迁移能力。相比之下，CD8CD226 T细胞表现出耗竭的表型，Runt相关转录因子2（RUNX2）表达降低。白细胞介素-6（IL-6）和巨噬细胞炎性蛋白-1β（MIP-1β）水平升高与CD8CD226 T细胞频率呈负相关，可能导致CD226下调，这可能导致CLL中的T细胞功能障碍。我们的研究结果突出了CD8CD226RUNX2 T细胞在CLL中的关键作用，并表明它们的减少与疾病进展和不良临床结果相关。这项研究还强调了靶向IL-6和MIP-1β以保留多功能CD8CD226 T细胞作为一种有前景的免疫治疗策略的潜力。
