Coevolving JAK2V617F+relapsed AML and donor T cells with PD-1 blockade after stem cell transplantation: an index case.
Coevolving JAK2V617F+relapsed AML and donor T cells with PD-1 blockade after stem cell transplantation: an index case.
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干细胞移植后共同进化的JAK2V617F+复发性AML和PD-1阻断供体T细胞：一个指标病例
DOI：
10.1182/bloodadvances.2021004335
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发表时间：
2021-11-23
期刊：
影响因子：
7.5
通讯作者：
Wu CJ
中科院分区：
文献类型：
--
作者：
Penter L;Gohil SH;Huang T;Thrash EM;Schmidt D;Li S;Severgnini M;Neuberg D;Hodi FS;Livak KJ;Zeiser R;Bachireddy P;Wu CJ
纳武单抗应答的索引病例与AML原始细胞上改变的循环T细胞组成和异质性PD-L1表达相关。单细胞方法为细胞对移植/检查点阻断的反应和抗性机制提供了补充性见解。异基因造血干细胞移植（HSCT）后骨髓增生性肿瘤（MPN）的复发与不良结局相关，因为恢复有效的移植物抗白血病（GVL）反应的治疗方法仍不理想。通过JAK 2 V617 F突变的MPN中PD-L1的过表达的免疫逃逸为治疗性PD-1阻断提供了理论基础，实际上，已经观察到纳武单抗在HSCT后复发的MPN中的临床活性。阐明PD-1阻断后这些患者的反应特征可以为增强GVL的新治疗概念提供信息。在这里，我们报告了一个集成的高维分析，使用单细胞RNA测序，T细胞受体测序，细胞索引的转录组和表位的测序（CITE-seq），并使用测序法测定转座酶可接近的染色质（scATAC-seq），连同质谱细胞术，在6个时间点收集的外周血单核细胞中，以及HSCT后复发性MPN的指示病例对PD-1阻断的短暂应答后。在nivolumab输注之前，急性髓性白血病（AML）原始细胞表现出趋化因子的高表达，并且T细胞的特征在于干扰素应答基因的表达。该基线炎症特征在纳武单抗输注后消失。临床应答的特征为多克隆CD 4 + T细胞群的瞬时扩增和AML亚群的收缩，AML亚群表现出巨核细胞特征和PD-L1表达升高。在复发时，具有祖细胞样特征的AML亚群的比例逐渐增加，表明AML原始细胞和供体来源的T细胞的共同进化。因此，我们证明了单细胞技术如何为PD-1阻断反应的细胞机制提供补充性见解，从而激发了复发性骨髓疾病中GVL反应的未来纵向高维单细胞研究。
Index case of nivolumab response associated with altered circulating T-cell composition and heterogeneous PD-L1 expression on AML blasts. Single-cell approaches provide complementary insight into cellular mechanisms of response and resistance to transplant/checkpoint blockade. Relapse of myeloproliferative neoplasms (MPNs) after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with poor outcomes, as therapeutic approaches to reinstate effective graft-versus-leukemia (GVL) responses remain suboptimal. Immune escape through overexpression of PD-L1 in JAK2V617F-mutated MPN provides a rationale for therapeutic PD-1 blockade, and indeed, clinical activity of nivolumab in relapsed MPN post-HSCT has been observed. Elucidation of the features of response following PD-1 blockade in such patients could inform novel therapeutic concepts that enhance GVL. Here, we report an integrated high-dimensional analysis using single-cell RNA sequencing, T-cell receptor sequencing, cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), and assay for transposase-accessible chromatin using sequencing (scATAC-seq), together with mass cytometry, in peripheral blood mononuclear cells collected at 6 timepoints before, during, and after transient response to PD-1 blockade from an index case of relapsed MPN following HSCT. Before nivolumab infusion, acute myeloid leukemia (AML) blasts demonstrated high expression of chemokines, and T cells were characterized by expression of interferon-response genes. This baseline inflammatory signature disappeared after nivolumab infusion. Clinical response was characterized by transient expansion of a polyclonal CD4+ T-cell population and contraction of an AML subpopulation that exhibited megakaryocytic features and elevated PD-L1 expression. At relapse, the proportion of the AML subpopulation with progenitor-like features progressively increased, suggesting coevolution of AML blasts and donor-derived T cells. We thus demonstrate how single-cell technologies can provide complementary insight into cellular mechanisms underlying response to PD-1 blockade, motivating future longitudinal high-dimensional single-cell studies of GVL responses in relapsed myeloid disease.
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影响因子：
64.5
作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
通讯作者：
Minn AJ
影响因子：
3.1
作者：
Kroenig, Holger;Kremmler, Lukas;Blank, Christian U.
通讯作者：
Blank, Christian U.
影响因子：
20.3
作者：
Davids, Matthew S.;Kim, Haesook T.;Armand, Philippe
通讯作者：
Armand, Philippe
影响因子：
10.1
作者：
Hansmann，Leo;Han，Arnold;Davis，Mark M.
通讯作者：
Davis，Mark M.
DOI：
10.1056/nejmoa1601202
发表时间：
2016-07-14
期刊：
The New England journal of medicine
影响因子：
--
作者：
Davids MS;Kim HT;Bachireddy P;Costello C;Liguori R;Savell A;Lukez AP;Avigan D;Chen YB;McSweeney P;LeBoeuf NR;Rooney MS;Bowden M;Zhou CW;Granter SR;Hornick JL;Rodig SJ;Hirakawa M;Severgnini M;Hodi FS;Wu CJ;Ho VT;Cutler C;Koreth J;Alyea EP;Antin JH;Armand P;Streicher H;Ball ED;Ritz J;Bashey A;Soiffer RJ;Leukemia and Lymphoma Society Blood Cancer Research Partnership
通讯作者：
Leukemia and Lymphoma Society Blood Cancer Research Partnership