Work

HBx hijacks the miR‐19a‐3p/BAMBI/TGF‐β1 axis to impair the anti‐tumour activity of CD4 + T cells in diffuse large B‐cell lymphoma

Year: 2026

Type: article

Abstract: Background Hepatitis B virus (HBV) is clinically associated with poor prognosis in diffuse large B‐cell lymphoma (DLBCL), while cellular communication in the tumour microenvironment (TME) is recognized as a critical driver of tumour progression. Nevertheless, whether HBV infection mediates DLBCL cell‐immune cell crosstalk remains undefined, with the precise mechanisms and associated key molecules remaining elusive. Methods SsGSEA, Cox regression (univariate/multivariate), WGCNA, and Kaplan–Meier analyses identified prognostic immune subsets and miRNAs in HBV + DLBCL. Dual luciferase assay, qRT‐PCR, western blot, ChIP, Co‐IP, flow cytometry, enzyme‐linked immunosorbent assay, immunohistochemistry, and murine models were employed together to evaluate CD4 + T cell dysfunction in vitro and in vivo. ScRNA‐seq analyses encompassed clustering, pseudotemporal trajectory, and ligand–receptor networks to decode TME dynamics. Results TME profiling identified diminished CD4⁺ T cell infiltration as an independent predictor of poor survival in HBV⁺ DLBCL. Mechanistically, HBx‐mediated down‐regulation of miR‐19a‐3p activated the BAMBI/Wnt signalling pathway, thereby enhancing TGF‐β1 secretion and suppressing the anti‐tumour activity of CD4 + T cells. Single‐cell analysis revealed that BAMBI high DLBCL cells engage CD4 + T cells via TGFB1‐TGFBR2 pair, with TGFBR2 enriched in exhausted subsets of CD4 + T cells and shaping their dysfunctional fate. Therapeutic restoration of miR‐19a‐3p or blockade of TGF‐β reinforced the CD4⁺ T cell anti‐tumour activity and restrained the progression of HBx‐overexpressing DLBCL in vivo. Conclusions HBx promoted TGF‐β1 hypersecretion via miR‐19a‐3p repression‐mediated Wnt/β‐catenin activation, directly driving CD4 + T cell depletion and functional exhaustion in DLBCL. Our work provided important insights into the immune determinants of poor prognosis in HBV + DLBCL, highlighting the pivotal role of CD4 + T cell dysfunction in driving disease progression and adverse clinical outcomes. Highlights Reduced CD4 + T cell enrichment in the TME predicted poor survival in HBV + DLBCL. Down‐regulation of miR‐19a‐3p by HBx activated the BAMBI‐mediated Wnt signalling, amplifying TGF‐β1 secretion to suppress anti‐tumour activity of CD4⁺ T cells. The TGF‐B1/TGFBR2 pair mediated the HBV + DLBCL‐CD4 + T cell communication. Targeting TGF‐β or miR‐19a‐3p improved CD4 + T cell immunity to suppress HBV + DLBCL progression

Source: Clinical and Translational Medicine

DOI: 10.1002/ctm2.70578