Research Paper Volume 13, Issue 10 pp 14131—14158

Downregulation of USP18 reduces tumor-infiltrating activated dendritic cells in extranodal diffuse large B cell lymphoma patients

Chong Zhao1, *, , Runzhi Huang2,3, *, , Zhiwei Zeng4, *, , Shaoxin Yang1, , Wei Lu1, , Jiali Liu5, , Yanyu Wei1, , Hezhou Guo1, , Yanjie Zhang1, , Penghui Yan4, &, , Zongqiang Huang4, , Jun Shi1, ,

  • 1 Department of Hematology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  • 2 Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
  • 3 Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai, China
  • 4 Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
  • 5 Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
* Equal contribution and co-first authors

Received: July 13, 2020       Accepted: March 29, 2021       Published: May 17, 2021
How to Cite

Copyright: © 2021 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Extranodal diffuse large B cell lymphoma (EN DLBCL) often leads to poor outcomes, while the underlying mechanism remains unclear. As immune imbalance plays an important role in lymphoma pathogenesis, we hypothesized that immune genes might be involved in the development of EN DLBCL. Ninety-three differentially expressed immune genes (DEIGs) were identified from 1168 differentially expressed genes (DEGs) between tumor tissues of lymph node DLBCL (LN DLBCL) and EN DLBCL patients in TCGA database. Nine prognostic immune genes were further identified from DEIGs by univariate Cox regression analysis. A multivariate predictive model was established based on these prognostic immune genes. Patients were divided into high- and low-risk groups according to the median model-based risk score. Kaplan-Meier survival curves showed that patients in the high-risk group had a shorter survival time than those in the low-risk group (P < 0.001). Ubiquitin-specific peptidase 18 (USP18) was further recognized as the key immune gene in EN DLBCL on the basis of coexpression of differentially expressed transcription factors (DETFs) and prognostic immune genes. USP18 exhibited low expression in EN DLBCL, which was regulated by LIM homeobox 2 (LHX2) (R = 0.497, P < 0.001, positive). The potential pathway downstream of USP18 was the MAPK pathway, identified by gene set variation analysis (GSVA), gene set enrichment analysis (GSEA) and Pearson correlation analysis (R = 0.294, P < 0.05, positive). The “ssGSEA” algorithm and Pearson correlation analysis identified that activated dendritic cells (aDCs) were the cell type mostly associated with USP18 (R = 0.694, P < 0.001, positive), indicating that USP18 participated in DC-modulating immune responses. The correlations among key biomarkers were supported by multiomics database validation. Indeed, the USP18 protein was confirmed to be expressed at lower levels in tumor tissues in patients with EN DLBCL than in those with LN DLBCL by immunohistochemistry. In short, our study illustrated that the downregulation of USP18 was associated with reduced aDC number in the tumor tissues of EN DLBCL patients, indicating that targeting USP18 might serve as a promising therapy.


AUC: Area under the curve; aDC: Activated dendritic cells; CCL1: C-C motif chemokine ligand 1; CHST7: Carbohydrate sulfotransferase 1; CNS: Central nervous system; DLBCL: Diffuse large B-cell lymphoma; EN DLBCL: Extranodal DLBCL; ENI: Extranodal involvement; DEGs: Differentially expressed genes; GO: Go ontology; GSVA: Gene set variation analysis; GCNT1: Glucosaminyl (N-Acetyl) transferase 1; IFNA21: Interferon alpha-21; IL2RA: Interleukin 2 receptor subunit alpha; IL5RA: Interleukin 5 receptor subunit alpha; IL21R: Interleukin 21 receptor; KEGG: Kyoto encyclopedia of genes and genomes; LN DLBCL: Lymphnode DLBCL; LHX2: LIM homeobox 2; MAPK: Mitogen-activated protein kinase; TLR7: Toll like receptor 7; USP18: Ubiquitin specific peptidase 18.