基质金属蛋白酶9相关肿瘤干细胞、CCL1沉默的树突状细胞和细胞因子诱导的杀伤细胞通过激活T细胞对急性髓系白血病具有显著的治疗效果。

MMP9-Associated Tumor Stem Cells, CCL1-Silenced Dendritic Cells, and Cytokine-Induced Killer Cells Have a Remarkable Therapeutic Efficacy for Acute Myeloid Leukemia by Activating T Cells.

作者信息

Dong Min, Zhang Guozhen, Meng Jie, Liu Biou, Jiang Duanfeng, Liu Feng

机构信息

Department of Hematology, The Second Affiliated Hospital of Hainan Medical University, Haikou 570000, China.

Department of Hematology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China.

出版信息

Stem Cells Int. 2023 May 9;2023:2490943. doi: 10.1155/2023/2490943. eCollection 2023.

DOI:10.1155/2023/2490943

PMID:37200633

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10188259/

Abstract

PURPOSE

Dendritic cells (DC) are specialized antigen-presenting cells, and cytokine-induced killer (CIK) cells have a specific killing activity to a variety of tumors. However, the underlining mechanism and function of DC-CIK cells in acute myeloid leukemia (AML) remain largely elusive.

METHODS

Gene expression profiles of leukemia patients were obtained from TCGA, DC cell components were evaluated using the quanTIseq method, and cancer stem cell scores were estimated using machine learning methods. The transcriptomes were obtained in DC-CIK cells from normal and AML patients by high-throughput sequencing. Large differentially expressed mRNAs were verified by RT-qPCR assay, and MMP9 and CCL1 were selected for subsequent studies and experiments.

RESULTS

Significant positive correlations were found with DC versus cancer stem cells ( = 0.008) and the expression of MMP9 versus cancer stem cells ( = 0.018). MMP9 and CCL1 were found to be highly expressed in DC-CIK cells from AML patients. DC-CIK cells with MMP9 and CCL1 knockout alone had little effect on leukemia cells, while knockdown of MMP9 and CCL1 in DC-CIK cells increased cytotoxicity, suppressed proliferation, and induced apoptosis of leukemia cells. In addition, we proved that MMP9- and CCL1-silenced DC-CIK cells significantly elevated the CDCD and CDCD cells and lowered the CD4PD-1 and CD8PD-1 T cells. Meanwhile, blockage of MMP9 and CCL1 in DC-CIK cells dramatically increased IL-2 and IFN-, increased CD107aþ (LAMP-1) and granzyme B (GZMB), and downregulated PD-1, CTLA4, TIM3, and LAG3 T cells from AML patients and AML model mice. Furthermore, activated T cells in DC-CIK cells knocking down MMP9 and CCL1 also prevented proliferation and accelerated apoptosis of AML cells.

CONCLUSION

Our findings demonstrated that blockage of MMP9 and CCL1 in DC-CIK cells could markedly enhance the therapeutic efficiency in AML via activating T cells.

摘要

目的

树突状细胞（DC）是专门的抗原呈递细胞，细胞因子诱导的杀伤细胞（CIK）对多种肿瘤具有特异性杀伤活性。然而，DC-CIK细胞在急性髓系白血病（AML）中的潜在机制和功能在很大程度上仍不清楚。

方法

从TCGA获得白血病患者的基因表达谱，使用quanTIseq方法评估DC细胞成分，并使用机器学习方法估计癌症干细胞评分。通过高通量测序在正常和AML患者的DC-CIK细胞中获得转录组。通过RT-qPCR测定验证大量差异表达的mRNA，并选择MMP9和CCL1进行后续研究和实验。

结果

发现DC与癌症干细胞之间存在显著正相关（=0.008），MMP9的表达与癌症干细胞之间存在显著正相关（=0.018）。发现MMP9和CCL1在AML患者的DC-CIK细胞中高表达。单独敲除MMP9和CCL1的DC-CIK细胞对白血病细胞几乎没有影响，而在DC-CIK细胞中敲低MMP9和CCL1可增加细胞毒性、抑制增殖并诱导白血病细胞凋亡。此外，我们证明沉默MMP9和CCL1的DC-CIK细胞显著提高了CDCD和CDCD细胞水平，并降低了CD4PD-1和CD8PD-1 T细胞水平。同时，在DC-CIK细胞中阻断MMP9和CCL1可显著增加IL-2和IFN-，增加CD107aþ（LAMP-1）和颗粒酶B（GZMB），并下调AML患者和AML模型小鼠的PD-1、CTLA4、TIM3和LAG3 T细胞。此外，敲低MMP9和CCL1的DC-CIK细胞中的活化T细胞也可阻止AML细胞的增殖并加速其凋亡。