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Abstract：
Unlike many other hematologic malignancies, Richter syndrome (RS), an aggressive B cell lymphoma originating from indolent chronic lymphocytic leukemia, is responsive to PD-1 blockade. To discover the determinants of response, we analyze single-cell transcriptome data generated from 17 bone marrow samples longitudinally collected from 6 patients with RS. Response is associated with intermediate exhausted CD8 effector/effector memory T cells marked by high expression of the transcription factor ZNF683, determined to be evolving from stem-like memory cells and divergent from terminally exhausted cells. This signature overlaps with that of tumor-infiltrating populations from anti-PD-1 responsive solid tumors. ZNF683 is found to directly target key T cell genes (TCF7, LMO2, CD69) and impact pathways of T cell cytotoxicity and activation. Analysis of pre-treatment peripheral blood from 10 independent patients with RS treated with anti-PD-1, as well as patients with solid tumors treated with anti-PD-1, supports an association of ZNF683high T cells with response.
摘要：
与许多其他血液系统恶性肿瘤不同，Richter综合征(RS),起源于惰性慢性淋巴细胞白血病的侵袭性B细胞淋巴瘤，对PD-1封锁有反应。为了发现反应的决定因素，我们分析了从6例RS患者纵向收集的17份骨髓样本中产生的单细胞转录组数据.应答与以转录因子ZNF683的高表达为标志的中等耗竭CD8效应物/效应物记忆T细胞相关,所述转录因子ZNF683被确定为从干细胞样记忆细胞进化并且与终末耗竭细胞不同。该特征与来自抗PD-1反应性实体瘤的肿瘤浸润群体的特征重叠。发现ZNF683直接靶向关键T细胞基因(TCF7、LMO2、CD69)并影响T细胞的细胞毒性和活化途径。来自10名用抗PD-1治疗的RS独立患者以及用抗PD-1治疗的实体瘤患者的治疗前外周血的分析支持ZNF683高T细胞与应答的关联。
