Shi Shaojie, Xing Haiyan, Xu Xiangping, Chai Jinquan, Lu Zixuan, Wang Jianyong, Wang Bin
Department of Immunology, Binzhou Medical University, Yantai, China.
Department of Allergy, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, China.
Int Immunopharmacol. 2024 May 10;132:111972. doi: 10.1016/j.intimp.2024.111972. Epub 2024 Apr 2.
The potential of cytotoxic CD4 T cells and tissue resident memory T cells (Trm) in achieving adult leukemia remission have been highlighted [1,2]. We hypothesized that CXCR6 could serve as a marker for cytotoxic CD4 Trm cells in the bone marrow (BM) of pediatric B-ALL patients. Flow cytometry (FCM) and published single cell RNA sequencing (scRNA-seq) datasets were employed to characterize CXCR6CD4 T cells in the BM and peripheral blood (PB) of pediatric B-ALL patients and healthy donors. FCM, scRNA-seq and co-culture were utilized to explore the cytotoxicity of CXCR6CD4 T cells in vitro based on in vitro induction of CXCR6CD4 T cells using tumor antigens and peripheral blood mononuclear cells (PBMCs). The ssGSEA based on the cell markers identified according to the in vivo scRNA-seq data, the TARGET-ALL-P2 datasets, and integrated machine learning algorithm were employed to figure out the key cells with prognostic values, followed by simulation of adoptive cell transfer therapy (ACT). Integrated machine learning identified the high-risk cells for disease free survival, and overall survival, while simulation of ACT therapy using CXCR6CD4T cells indicated that CXCR6CD4 T cells could remodel the bone marrow microenvironments towards anti-tumor. Based on the expression of genes involved in formation of resident memory T cells, CXCR6 is not a marker of resident memory CD4T cells but defines therapeutic subtypes of CD4 cytotoxic T cell lineage for pediatric B-ALL.
细胞毒性CD4 T细胞和组织驻留记忆T细胞（Trm）在实现成人白血病缓解方面的潜力已得到凸显[1,2]。我们假设CXCR6可作为儿童B淋巴细胞白血病（B-ALL）患者骨髓（BM）中细胞毒性CD4 Trm细胞的标志物。运用流式细胞术（FCM）和已发表的单细胞RNA测序（scRNA-seq）数据集，对儿童B-ALL患者及健康供体骨髓和外周血（PB）中的CXCR6⁺CD4 T细胞进行表征。基于使用肿瘤抗原和外周血单个核细胞（PBMCs）体外诱导CXCR6⁺CD4 T细胞，运用FCM、scRNA-seq和共培养方法在体外探究CXCR6⁺CD4 T细胞的细胞毒性。基于根据体内scRNA-seq数据、TARGET-ALL-P2数据集鉴定的细胞标志物以及集成机器学习算法的单样本基因集富集分析（ssGSEA），用于找出具有预后价值的关键细胞，随后模拟过继性细胞转移疗法（ACT）。集成机器学习确定了无病生存和总生存的高危细胞，而使用CXCR6⁺CD4 T细胞模拟ACT疗法表明，CXCR6⁺CD4 T细胞可使骨髓微环境向抗肿瘤方向重塑。基于参与驻留记忆T细胞形成的基因表达，CXCR6不是驻留记忆CD4 T细胞的标志物，而是定义了儿童B-ALL的CD4细胞毒性T细胞谱系的治疗亚型。
