Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
Exp Biol Med (Maywood). 2024 Sep 23;249:10155. doi: 10.3389/ebm.2024.10155. eCollection 2024.
Tumor immune microenvironment is crucial for diffuse large B-cell lymphoma (DLBCL) development. However, the mechanisms by which super-enhancers (SEs) regulate the interactions between DLBCL cells and tumor-infiltrating immune cells remains largely unknown. This study aimed to investigate the role of SE-controlled genes in regulating the interactions between DLBCL cells and tumor-infiltrating immune cells. Single-cell RNA-seq, bulk RNA-seq and H3K27ac ChIP-seq data were downloaded from the Heidelberg Open Research Data database and Gene Expression Omnibus database. HOMER algorithm and Seurat package in R were used for bioinformatics analysis. Cell proliferation and lactate dehydrogenase (LDH) release was detected by MTS and LDH release assays, respectively. Interaction between B cell cluster and CD8 T cell and NK cell cluster was most obviously enhanced in DLBCL, with CD70-CD27, MIF-CD74/CXCR2 complex, MIF-CD74/CD44 complex and CCL3-CCR5 interactions were significantly increased. NK cell sub-cluster showed the strongest interaction with B cell cluster. ZZZ3 upregulated the transcription of by binding to its SE. Silencing CD70 in DOHH2 cells significantly promoted the proliferation of co-cultured NK92 cells and LDH release from DOHH2 cells, which was counteracted by ZZZ3 overexpression in DOHH2 cells. CD70 silencing combined with PD-L1 blockade promoted LDH release from DOHH2 cells co-cultured with NK92 cells. In conclusion, DLBCL cells inhibited the proliferation and killing of infiltrating NK cells by regulating ZZZ3/CD70 axis. Targeting ZZZ3/CD70 axis combined with PD-L1 blockade is expected to be a promising strategy for DLBCL treatment.
肿瘤免疫微环境对弥漫性大 B 细胞淋巴瘤（DLBCL）的发展至关重要。然而，超增强子（SEs）调控 DLBCL 细胞与肿瘤浸润免疫细胞相互作用的机制在很大程度上尚不清楚。本研究旨在探讨 SE 调控基因在调控 DLBCL 细胞与肿瘤浸润免疫细胞相互作用中的作用。从海德堡开放研究数据数据库和基因表达综合数据库下载单细胞 RNA-seq、批量 RNA-seq 和 H3K27ac ChIP-seq 数据。使用 HOMER 算法和 R 中的 Seurat 包进行生物信息学分析。通过 MTS 和 LDH 释放测定分别检测细胞增殖和乳酸脱氢酶（LDH）释放。在 DLBCL 中，B 细胞簇与 CD8 T 细胞和 NK 细胞簇之间的相互作用最明显增强，CD70-CD27、MIF-CD74/CXCR2 复合物、MIF-CD74/CD44 复合物和 CCL3-CCR5 相互作用明显增加。NK 细胞亚群与 B 细胞簇的相互作用最强。ZZZ3 通过与 SE 结合上调的转录。在 DOHH2 细胞中沉默 CD70 显著促进共培养的 NK92 细胞的增殖和 DOHH2 细胞中 LDH 的释放，而 DOHH2 细胞中 ZZZ3 的过表达则拮抗了这一作用。CD70 沉默联合 PD-L1 阻断促进了与 NK92 细胞共培养的 DOHH2 细胞中 LDH 的释放。综上所述，DLBCL 细胞通过调节 ZZZ3/CD70 轴抑制浸润 NK 细胞的增殖和杀伤。靶向 ZZZ3/CD70 轴联合 PD-L1 阻断有望成为治疗 DLBCL 的一种有前途的策略。
