大约三分之一的弥漫性大B细胞淋巴瘤（DLBCL）患者表现出 MYC 和 BCL2 的共表达（双表达淋巴瘤，DEL），预后不良。应用 venetoclax（ABT-199）有针对性地抑制抗凋亡蛋白BCL2，在多种B细胞恶性肿瘤中已获批准，并正在临床试验中研究DLBCL。BCL2的抗凋亡功能是否代表DEL-DLBCL的多面性易感特征，影响瘤内微环境中的淋巴瘤B细胞和T细胞，有待阐明。在这里，我们提供了新型的基因工程小鼠，可临床再现DEL-DLBCL的淋巴瘤发生，并评估它们对venetoclax和抗CD20标准免疫治疗的敏感性和生存率。venetoclax治疗通过授权其固有启动的细胞凋亡，对MYC+ / BCL2+的淋巴瘤细胞进行特异性杀伤，并通过丰富特异性抗原激活的浸润瘤的效应型CD8 T细胞，表现出先前未被认可的免疫调节活性。虽然DEL-DLBCL小鼠对单独的venetoclax无效，但抑制BCL2显著延长了与鼠源替代品抗CD20 rituximab同时治疗的小鼠总生存率。这些结果表明，抗CD20标准免疫治疗和BCL2抑制的联合作用导致协同的免疫调节效应和改善的临床前反应，这可能为DEL-DLBCL患者提供有前途的治疗机会。©作者（或其雇主）2023年。CC BY-NC下允许复用。不得商业再利用。由BMJ出版。

Approximately one-third of diffuse large B cell lymphoma (DLBCL) patients exhibit co-expression of MYC and BCL2 (double-expressor lymphoma, DEL) and have a dismal prognosis. Targeted inhibition of the anti-apoptotic protein BCL2 with venetoclax (ABT-199) has been approved in multiple B-cell malignancies and is currently being investigated in clinical trials for DLBCL. Whether BCL2 anti-apoptotic function represents a multifaceted vulnerability for DEL-DLBCL, affecting both lymphoma B cells and T cells within the tumor microenvironment, remains to be elucidated.Here, we present novel genetically engineered mice that preclinically recapitulate DEL-DLBCL lymphomagenesis, and evaluate their sensitivity ex vivo and in vivo to the promising combination of venetoclax with anti-CD20-based standard immunotherapy.Venetoclax treatment demonstrated specific killing of MYC+/BCL2+ lymphoma cells by licensing their intrinsically primed apoptosis, and showed previously unrecognized immunomodulatory activity by specifically enriching antigen-activated effector CD8 T cells infiltrating the tumors. Whereas DEL-DLBCL mice were refractory to venetoclax alone, inhibition of BCL2 significantly extended overall survival of mice that were simultaneously treated with a murine surrogate for anti-CD20 rituximab.These results suggest that the combination of anti-CD20-based immunotherapy and BCL2 inhibition leads to cooperative immunomodulatory effects and improved preclinical responses, which may offer promising therapeutic opportunities for DEL-DLBCL patients.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.