The EZH2 inhibitor tazemetostat upregulates the expression of CCL17/TARC in B‐cell lymphoma and enhances T‐cell recruitment

• DOI: 10.1111/cas.15122
• Publication Date: 2021-08-27T18:25:01Z
• Authors: Hepei Yuan; Momoko Nishikori; Yasuyuki Otsuka; Hiroshi Arima; Toshio Kitawaki; Akifumi Takaori‐K...
• Keywords: Jumonji Domain-Containing Histone Demethylases; Databases, Factual; Pyridones; EZH2 inhibitor; Morpholines; 03 medical and health sciences; Lymphocytes, Tumor-Infiltrating; CCL17; Cell Movement; Cell Line, Tumor; Tumor Microenvironment; tumor microenvironment; Humans; Enhancer of Zeste Homolog 2 Protein; Reed-Sternberg Cells; Promoter Regions, Genetic; 0303 health sciences; B-cell lymphoma; Biphenyl Compounds; Original Articles; Up-Regulation; 3. Good health; Benzamides; Chemokine CCL17; Lymphoma, Large B-Cell, Diffuse; Hodgkin lymphoma

AbstractAn inhibitor of the histone methyltransferase enhancer of zeste homologue 2 (EZH2), tazemetostat, has been developed for the treatment of B‐cell lymphoma, but its mechanisms of action are not fully elucidated. We screened for genes targeted by tazemetostat in eleven B‐cell lymphoma cell lines and found that tazemetostat significantly increased the expression of chemokine (C‐C motif) ligand 17 (CCL17)/thymus‐ and activation‐regulated chemokine (TARC) in all, which codes for a chemokine that is a hallmark of Hodgkin/Reed‐Sternberg (H/RS) cells in Hodgkin lymphoma. Notably, gene set enrichment analysis demonstrated a positive correlation between the genes upregulated by tazemetostat in five follicular lymphoma (FL) cell lines and those reported to be overexpressed in H/RS cells. The CCL17 promoter region was enriched in repressive histone modification H3K27me3, and tazemetostat induced H3K27 demethylation and activated gene transcription. CCL17 protein secretion was also induced by EZH2 inhibition, which was further enhanced by concurrent CpG stimulation. In vitro transwell migration assay demonstrated that CCL17 produced by tazemetostat‐treated B cells enhanced the recruitment of T cells, which had the potential to exert antilymphoma response. Analysis of publicly available human lymphoma databases showed that CCL17 gene expression was inversely correlated with the EZH2 activation signature and significantly paralleled the CD4+ and CD8+ T‐cell–rich signature in FL and germinal center B‐cell–like diffuse large B‐cell lymphoma. Our findings indicate that tazemetostat can potentially activate antilymphoma response by upregulating CCL17 expression in B‐cell lymphoma cells and promote T‐cell recruitment, which provides a rationale for its combination with immunotherapy.