Human endogenous retroviruses as epigenetic therapeutic targets in TP53-mutated diffuse large B-cell lymphoma

Abstract

TP53 mutation (TP53mut) occurs in 10–20% of diffuse large B-cell lymphoma (DLBCL) cases and serves as an unfavorable biomarker of DLBCL progression. It confers resistance to immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation, and anti-CD19 chimeric antigen receptor T-cell therapy. Therapeutic targeting of TP53mut remains a significant challenge in DLBCL treatment. Here we assessed TP53mut in 667 patients with newly diagnosed DLBCL, including 576 patients treated with immunochemotherapy rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 91 patients with decitabine plus R-CHOP (DR-CHOP, NCT02951728 and NCT04025593). TP53mut independently predicted an inferior prognosis in R-CHOP-treated DLBCL, although this could be mitigated by DR-CHOP treatment. In TP53mut patients, multiple viral regulation pathways were repressed, resulting in the inhibition of immune modulation, as revealed by gene set enrichment analysis. TP53mut DLBCL exhibited 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 down-regulated SUV39H1, inhibited H3K9me3 occupancy on ERVs, and triggered ERV expression, thereby unleashing interferons program and CD4+T/CD8+T cell activation. Molecular silencing of SUV39H1 significantly abrogated decitabine-induced H3K9me3 inhibition and ERV expression. In TP53mut patient-derived xenograft models and TP53mut patients, the anti-tumor effect was improved upon the use of combined treatment of decitabine and doxorubicin via SUV39H1-H3K9me3-ERVs axis. Collectively, our findings highlight an ERV regulatory circuitry in TP53mut DLBCL and the crucial roles ERVs for epigenetically reprogramming tumor microenvironment for treating TP53mut-driven cancers.

Molecular Subtypes and the Role of TP53 in Diffuse Large B-Cell Lymphoma and Richter Syndrome

“…In addition, uneven distribution among LME categories was observed for some common mutations and copy number alterations (CNAs), suggesting that the changes in the lymphoma microenvironment are primarily influenced by the genetic factors pertaining to the lymphoma cells themselves. This possibility is further supported by studies showing that specific genetic lesions that define or are over-represented in certain DLBCL genetic subtypes, such as mutations in TP53, NOTCH1, CREBBP, or NFKBIE, can induce changes in the composition or functionality of TME cells that characterize some of the LME categories [ 57 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ]. Such changes include low infiltration of CD4+ T cells and CD8+ T cells or reduced T-cell cytolytic activity due to immune exhaustion, which are features of the DP and IN category, respectively, and can contribute to the immune escape of the malignant B cells by disrupting T cell-mediated antitumor immune surveillance mechanisms.…”

“…To further investigate whether the identified overrepresented pathways could guide targeted therapy of the different genetic subtypes of DLBCL, R-CHOP was compared to R-CHOP in combination with a targeted agent in the genetic subtype-guided immunochemotherapy GUIDANCE-01 trial, where a simplified 20-gene algorithm was used to stratify patients in accordance with the classifier of Staudt et al [ 56 ]. The targeted agents included the histone deacetylase (HDAC) inhibitor tucidinostat, which was utilized for the EZB-like subtype because epigenetic alterations are a defining feature of the EZB-type tumors; ibrutinib, which was utilized for the BTK-dependent subtypes MCD-like and BN2-like; and the demethylating agent decitabine, which was utilized for the TP53-mutated subtype, based on its effect in counteracting the immune depletion of the microenvironment associated with TP53-mutated tumors [ 57 , 58 , 59 ]. Lastly, lenalidomide, an immunomodulatory drug, was utilized for the N1-like subtype and the unclassified patients based on the improved outcome of the lenalidomide + R-CHOP combination in two previous clinical trials of patients with DLBCL and because of the unavailability of a specific targeting agent for patients belonging to these genetic categories [ 60 , 61 ].…”

“…Dysregulation and depletion of the TME is a well-documented feature of TP53 -mutated DLBCL [ 57 , 58 , 63 , 64 , 158 ]. Consistent with the potential role of TP53 in shaping the immune microenvironment of the tumor, TP53 alterations in lymphomas are associated with reduced activity and migration of CAR-T cells and serve as a potent predictor of anti-CD19 CAR-T failure [ 158 ].…”

Endogenous Retroviruses Unveiled: A Comprehensive Review of Inflammatory Signaling/Senescence-Related Pathways and Therapeutic Strategies

“…The TP53 mutation serves as an adverse prognostic indicator in diffuse large B-cell lymphoma (DLBCL), conferring resistance to conventional therapies such as chemotherapy. Studies have demonstrated that TP53 mutation upregulates the H3K9 methyltransferase SUV39H1, leading to the inhibition of HERV expression via histone methylation [171,172]. Decitabine administration can counteract this mechanism, enhancing HERV expression, stimulating interferon release, and slowing down tumor advancement [172,173].…”

“…Studies have demonstrated that TP53 mutation upregulates the H3K9 methyltransferase SUV39H1, leading to the inhibition of HERV expression via histone methylation [171,172]. Decitabine administration can counteract this mechanism, enhancing HERV expression, stimulating interferon release, and slowing down tumor advancement [172,173]. Various approaches to combined drug administration are presented in Table 2.…”