ZNF683标记了与PD-1抗体治疗Richter综合征后的抗肿瘤免疫相关的CD8+ T细胞亚群。
ZNF683 marks a CD8+ T cell population associated with anti-tumor immunity following anti-PD-1 therapy for Richter syndrome.
发表日期：2023 Sep 19
作者：
Erin M Parry, Camilla K Lemvigh, Stephanie Deng, Nathan Dangle, Neil Ruthen, Binyamin A Knisbacher, Julien Broséus, Sébastien Hergalant, Romain Guièze, Shuqiang Li, Wandi Zhang, Connor Johnson, Jaclyn Long, Shanye Yin, Lillian Werner, Annabelle Anandappa, Noelia Purroy, Satyen Gohil, Giacomo Oliveira, Pavan Bachireddy, Sachet A Shukla, Teddy Huang, Joseph D Khoury, Beenu Thakral, Michael Dickinson, Constantine Tam, Kenneth J Livak, Gad Getz, Donna Neuberg, Pierre Feugier, Peter Kharchenko, William Wierda, Lars Rønn Olsen, Nitin Jain, Catherine J Wu
来源：
CANCER CELL
摘要：
与许多其他血液系统恶性肿瘤不同，Richter综合征（RS）是一种来源于慢性淋巴细胞白血病的侵袭性B细胞淋巴瘤，对PD-1阻断有响应。为了发现响应的决定因素，我们分析了来自6名RS患者的17个骨髓样本所产生的单细胞转录组数据。响应与中度耗竭的CD8效应器/效应器记忆T细胞相关，这些细胞具有高表达转录因子ZNF683的特征，被确定为从干细胞式记忆细胞进化而来，与终末耗竭细胞不同。这个特征与抗PD-1治疗响应性固体肿瘤中的肿瘤浸润T细胞人群重叠。发现ZNF683直接靶向关键的T细胞基因（TCF7，LMO2，CD69）并影响T细胞的细胞毒性和激活通路。对经过抗PD-1治疗的独立RS患者的10个治疗前外周血样本以及接受抗PD-1治疗的实体肿瘤患者的分析，支持了ZNF683高表达的T细胞与响应之间的关联。版权所有 © 2023 Elsevier Inc. 保留所有权利。
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.Copyright © 2023 Elsevier Inc. All rights reserved.