所有扩散性大B细胞淋巴瘤（DLBCLs）中有大约一半被大量的调节性T细胞（Tregs）浸润。尽管特别是“效应器”Tregs的存在与采用标准的利妥昔单抗加环磷酰胺、多柔比星、长春瑰菜碱和泼尼松（R-CHOP）免疫化疗治疗的患者不良预后有关，但这种细胞类型在淋巴瘤发生和进展中的作用尚不清楚。在这里，我们使用含有预期收集的DLBCL患者标本的组织微阵列，以及来自公开可用队列的数据，探索Treg浸润的DLBCL的突变谱系。我们进一步利用MYC驱动淋巴瘤模型来机械性地分析Treg对淋巴瘤发病机制的贡献，并开发Treg选择性白细胞介素-2（IL-2）饥饿策略，以改善MYC驱动淋巴瘤的免疫控制。我们发现，除了一种特征为并存MYD88 / CD79突变的亚型外，所有遗传性DLBCL亚型都受到Treg的严重浸润。光谱流式细胞术和单细胞RNA测序揭示了Treg对MYC驱动淋巴瘤浸润具有功能性和免疫抑制标记的强烈表达；值得注意的是，我们发现肿瘤接触时的内部性Treg来自于CD4 +幼稚祖细胞的局部转化。 Foxp3iDTR小鼠中的Treg消融，或通过抗体介导的Treg选择性阻断IL-2信号来强烈降低淋巴瘤负担。我们确定淋巴瘤B细胞是IL-2的主要来源，并显示Treg清除同时清除Foxp3-阴性CD4 + T细胞，而不是CD8 + T细胞或自然杀伤T（NK）细胞。 Tregs对ATP水解和腺苷生产的抑制至少部分呈现出Treg消除的效果。 Treg消融进一步与促凋亡的CD40激活相辅相成，以保持持久的反应。综合数据表明，Treg是DLBCL的潜在治疗靶点，特别是与其他免疫治疗联合使用。 ©作者（或他们的雇主）2023年。在CC BY-NC下允许再利用。不能进行商业再利用。由BMJ出版。

Roughly half of all diffuse large B-cell lymphomas (DLBCLs) are infiltrated by large numbers of regulatory T-cells (Tregs). Although the presence of 'effector' Tregs in particular is associated with an inferior prognosis in patients on standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy, the role of this cell type during lymphoma initiation and progression is poorly understood.Here, we use tissue microarrays containing prospectively collected DLBCL patient specimens, as well as data from publicly available cohorts to explore the mutational landscape of Treg-infiltrated DLBCL. We further take advantage of a model of MYC-driven lymphoma to mechanistically dissect the contribution of Tregs to lymphoma pathogenesis and to develop a strategy of Treg-selective interleukin-2 (IL-2) starvation to improve immune control of MYC-driven lymphoma.We find that all genetic DLBCL subtypes, except for one characterized by co-occurring MYD88/CD79 mutations, are heavily infiltrated by Tregs. Spectral flow cytometry and scRNA-sequencing reveal the robust expression of functional and immunosuppressive markers on Tregs infiltrating MYC-driven lymphomas; notably, we find that intratumoral Tregs arise due to local conversion from naïve CD4+ precursors on tumor contact. Treg ablation in Foxp3iDTR mice, or by antibody-mediated Treg-selective blockade of IL-2 signaling, strongly reduces the lymphoma burden. We identify lymphoma B-cells as a major source of IL-2, and show that the effects of Treg depletion are reversed by the simultaneous depletion of Foxp3-negative CD4+ T-cells, but not CD8+ T-cells or natural killer (NK) cells. The inhibition of ATP hydrolyzation and adenosine production by Tregs at least partly phenocopies the effects of Treg depletion. Treg depletion further synergizes with pro-apoptotic CD40 activation to sustain durable responses.The combined data implicate Tregs as a potential therapeutic target in DLBCL, especially in combination with other immunotherapies.© 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.