GPCR signaling contributes to immune characteristics of microenvironment and process of EBV-induced lymphomagenesis

Sci Bull (Beijing). 2023 Nov 15;68(21):2607-2619. doi: 10.1016/j.scib.2023.09.029. Epub 2023 Sep 22.


Epstein-Barr virus (EBV) is the oncogenic driver of multiple cancers. However, the underlying mechanism of virus-cancer immunological interaction during disease pathogenesis remains largely elusive. Here we reported the first comprehensive proteogenomic characterization of natural killer/T-cell lymphoma (NKTCL), a representative disease model to study EBV-induced lymphomagenesis, incorporating genomic, transcriptomic, and in-depth proteomic data. Our multi-omics analysis of NKTCL revealed that EBV gene pattern correlated with immune-related oncogenic signaling. Single-cell transcriptome further delineated the tumor microenvironment as immune-inflamed, -deficient, and -desert phenotypes, in association with different setpoints of cancer-immunity cycle. EBV interacted with transcriptional factors to provoke GPCR interactome (GPCRome) reprogramming. Enhanced expression of chemokine receptor-1 (CCR1) on malignant and immunosuppressive cells modulated virus-cancer interaction on microenvironment. Therapeutic targeting CCR1 showed promising efficacy with EBV eradication, T-cell activation, and lymphoma cell killing in NKTCL organoid. Collectively, our study identified a previously unknown GPCR-mediated malignant progression and translated sensors of viral molecules into EBV-specific anti-cancer therapeutics.

Keywords: CCR1; Epstein-Barr virus; Lymphoma; Microenvironment; Multi-omics; Single-cell transcriptome.

MeSH terms

  • Epstein-Barr Virus Infections* / complications
  • Herpesvirus 4, Human / genetics
  • Humans
  • Lymphoma* / complications
  • Natural Killer T-Cells* / pathology
  • Proteomics
  • Tumor Microenvironment / genetics