Diffuse large B-cell lymphoma (DLBCL) is a common, genomically heterogenous disease that presents a clinical challenge despite the success of frontline regimens and second-line chimeric antigen receptor T-cell (CAR-T) therapy. Recently, genomic alterations and tumor microenvironment features associated with poor CAR-T response have been identified, namely those to the TP53 tumor suppressor gene. This retrospective analysis aimed to integrate various data to identify genomic partnerships capable of providing further clarity and actionable treatment targets within this population. Publicly available data were analyzed for differential expression based on TP53 and 24-month event-free survival (EFS24) status, revealing enrichments of the BRD4 bromodomain oncogene (p < 0.0001, p = 0.001). High-BRD4 and TP53 alterations were significantly associated with lower CDKN1A (p21) and TNFRSF10B (TRAIL-R2), a key tumor suppressor and CAR-T modulator, respectively. Significant loss of CD8 T-cell presence within low-TNFRSF0B (p = 0.0042) and altered-TP53 (p = 0.0424) patients showcased relevant outcome-associated tumor microenvironment features. Furthermore, reduced expression of CDKN1A was associated with low TNFRSF10B (FDR < 0.0001) and increased BRD4 interactant genes (FDR < 0.0001). Promisingly, in vitro MDM2 inhibition with Idasnutlin and TP53 reactivation via Eprenetapopt was able to renew TNFRSF10B protein expression. Additionally, applying the BRD4-degrading PROTAC ARV-825 and the CDK4/6 inhibitor Abemaciclib as single-agents and in synergistic combination significantly reduced TP53-altered DLBCL cell line viability. Our analysis presents key associations within a genomic network of actionable targets capable of providing clarity within the evolving precision CAR-T treatment landscape.

弥漫性大 B 细胞淋巴瘤 (DLBCL) 是一种常见的基因组异质性疾病，尽管一线治疗方案和二线嵌合抗原受体 T 细胞 (CAR-T) 疗法取得了成功，但仍面临临床挑战。最近，已经确定了与 CAR-T 反应不佳相关的基因组改变和肿瘤微环境特征，即TP53肿瘤抑制基因的改变和肿瘤微环境特征。这项回顾性分析旨在整合各种数据，以确定能够在该人群中提供进一步清晰度和可操作治疗目标的基因组伙伴关系。根据TP53和 24 个月无事件生存 (EFS24) 状态对公开数据进行差异表达分析，揭示了 BRD4 溴结构域癌基因的富集（ p < 0.0001， p = 0.001）。高 BRD4 和TP53改变分别与关键肿瘤抑制因子和 CAR-T 调节剂 CDKN1A (p21) 和 TNFRSF10B (TRAIL-R2) 的降低显着相关。低 TNFRSF0B ( p = 0.0042) 和改变的TP53 ( p = 0.0424) 患者中 CD8 T 细胞显着丧失，表现出与结果相关的肿瘤微环境特征。此外，CDKN1A 表达的减少与 TNFRSF10B 水平降低 (FDR < 0.0001) 和 BRD4 相互作用基因增加 (FDR < 0.0001) 相关。令人鼓舞的是，通过 Idasnutlin 体外抑制 MDM2 并通过 Eprenetapopt 重新激活 TP53 能够恢复 TNFRSF10B 蛋白表达。此外，将 BRD4 降解性 PROTAC ARV-825 和 CDK4/6 抑制剂 Abemaciclib 作为单药或协同组合使用，可显着降低TP53改变的 DLBCL 细胞系的活力。 我们的分析呈现了可操作靶点基因组网络中的关键关联，能够在不断发展的精准 CAR-T 治疗领域提供清晰的信息。