831P Decitabine sensitized TP53-mutated diffuse large B cell lymphoma to R-CHOP treatment via activation of endogenous retrovirus

TP53 mutations (TP53mut) occur in 10-20% of diffuse large B-cell lymphoma (DLBCL) and is an unfavorable biomarker of DLBCL progression, conferring resistance to immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation, and anti-CD19 chimeric antigen receptor T-cell therapy. How to target TP53mut remains a great challenge in treating DLBCL. Survival of 667 newly diagnosed DLBCL patients were assessed, including 576 patients with R-CHOP and 91 patients with decitabine plus R-CHOP (DR-CHOP, NCT02951728 and NCT04025593). RNA sequencing data from TP53mut and TP53wt DLBCL tumors were analyzed. To further elucidate the underlying mechanisms of decitabine sensitizing TP53mut DLBCL to R-CHOP treatment, TP53mut DLBCL cell lines (TP53mut p.R248Q, p.R273C and p.R175H ) and patient-derived xenograft models (PDX, p.R248Q, p.R273C and p.R175H) were established and treated with decitabine, or doxorubicin ± decitabine. TP53mut independently predicted inferior prognosis in R-CHOP-treated DLBCL, which could be counteracted by DR-CHOP treatment. In TP53mut patients, multiple viral regulation pathways were repressed, accompanied by inhibition of immune modulation. TP53mut DLBCL possessed increased methyltransferase SUV39H1 expression and H3K9 trimethylation (H3K9me3), contributing to repression of endogenous retroviruses (ERVs) and immunosuppressive tumor microenvironment. In TP53mut DLBCL cell lines, decitabine downregulated SUV39H1, inhibited H3K9me3 occupancy on ERVs, triggered ERV expression, thereby unleashed interferons program, and CD4+T/CD8+T cell activation. In TP53mut PDX models and TP53mut patients, improved anti-tumor effect was observed upon combined treatment of decitabine and doxorubicin via SUV39H1-H3K9me3-ERVs axis. The present study demonstrated decitabine induced a viral mimicry pathway with peripheral blood CD4+T/CD8+T cell activation in TP53mut DLBCL and sensitized TP53mut DLBCL to R-CHOP treatment. Our findings highlighted an ERV regulatory circuitry in TP53mut DLBCL and assigned essential roles of ERVs for epigenetic reprogramming tumor microenvironment in TP53mut-driven cancers.