Abstract 831P
Background
TP53 mutations (TP53 mut) 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 TP53 mut remains a great challenge in treating DLBCL.
Methods
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 TP53 mut and TP53 wt DLBCL tumors were analyzed. To further elucidate the underlying mechanisms of decitabine sensitizing TP53 mut DLBCL to R-CHOP treatment, TP53 mut DLBCL cell lines (TP53 mut 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.
Results
TP53 mut independently predicted inferior prognosis in R-CHOP-treated DLBCL, which could be counteracted by DR-CHOP treatment. In TP53 mut patients, multiple viral regulation pathways were repressed, accompanied by inhibition of immune modulation. TP53 mut DLBCL possessed increased methyltransferase SUV39H1 expression and H3K9 trimethylation (H3K9me3), contributing to repression of endogenous retroviruses (ERVs) and immunosuppressive tumor microenvironment. In TP53 mut 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 TP53 mut PDX models and TP53 mut patients, improved anti-tumor effect was observed upon combined treatment of decitabine and doxorubicin via SUV39H1-H3K9me3-ERVs axis.
Conclusions
The present study demonstrated decitabine induced a viral mimicry pathway with peripheral blood CD4+T/CD8+T cell activation in TP53 mut DLBCL and sensitized TP53 mut DLBCL to R-CHOP treatment. Our findings highlighted an ERV regulatory circuitry in TP53 mut DLBCL and assigned essential roles of ERVs for epigenetic reprogramming tumor microenvironment in TP53 mut-driven cancers.
Clinical trial identification
NCT02951728, NCT04025593.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Natural Science Foundation of China (81830007, 82130004, 82170178, 82200201 and 82070204), National Key R&D Program of China (2022YFC2502600), Chang Jiang Scholars Program, Shanghai Commission of Science and Technology (17PJ1405800), Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support (20152206, 20152208, and 20171902), Clinical Research Plan of Shanghai hospital development center (SHDC, 2020CR1032B), Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine (DLY201601), Samuel Waxman Cancer Research Foundation, and the Foundation of National Facility for Translational Medicine (Shanghai, TMSK-2020-115).
Disclosure
All authors have declared no conflicts of interest.
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