Hepatitis B Virus-Associated Follicular Lymphoma Reveals T-Cell Inflamed Phenotype and Response to Lenalidomide

Abstract

\n Background: Follicular lymphoma (FL) is a malignancy of lymphocytes derived from germinal center (GC). Hepatitis B virus (HBV) infection may increase the incidence of FL. Here, we performed an integrated genomic and transcriptomic analysis to identify molecular characteristics and therapeutic targets for HBV-associated FL.Methods: A total of 253 patients with newly diagnosed FL were enrolled. Whole-genome sequencing (n=13) and whole-exome sequencing (n=87) were performed on tumor samples of 100 patients. Among them, 84 patients were available for transcriptomic sequencing data. Moreover, biological function of immune modulator TNFAIP3 mutation was investigated in vitro using FL cell line SC-1 and in vivo using zebrafish xenograft model.Results: By characterizing altogether 253 FL patients, we showed that patients with HBV infection (surface antigen positive, HBsAg+) were significantly associated with younger age, more frequent spleen involvement, advanced histological grade, higher proliferation index, and poorer progression-free survival. By whole-genome/exome and targeted sequencing, we observed increased mutations in immune modulators (TNFAIP3, CD70, CXCR4, PIM1, KLF2, FAS, CD58, and CD83), decreased mutations in epigenetic modifiers (KMT2D and CREBBP), and low incidence of BCL2 translocation as the core oncogenic program of HBsAg+ FL. By transcriptomic sequencing, we further showed that HBsAg+ FL was enriched by immune-related pathways, antigen processing and presentation and IFN signatures, as well as inflamed signatures and infiltration of CD8+T and Th1 cells, with malignant lymphocytes transiting to post-GC phenotype. In the co-culture system of FL cell line SC-1 with peripheral blood mononuclear cells mimicking in vivo situation, TNFAIP3 mutations induced overexpression of TIGIT on CD8+T cells and VISTA on Th1 cells, both of which were downregulated by lenalidomide, resulting in sensitivity of TNFAIP3-mutant cells to lenalidomide treatment in co-culture system and in zebrafish xenograft model. Of note, negative prognostic impact of HBV infection on patients treated with rituximab-based immunochemotherapy could be overcome by rituximab and lenalidomide.Conclusions: HBV-associated FL may be considered as a specific subtype, based on distinct immune modulator mutations, and CD8+T- and Th1-enriched post-GC phenotype. Moreover, these findings provided new insights into the pathogenetic role of HBV in FL and the potential benefit of immunomodulatory agents in treating HBV-associated FL.