Single cell T cell landscape and T cell receptor repertoire profiling of AML in context of PD-1 blockade therapy.
Single cell T cell landscape and T cell receptor repertoire profiling of AML in context of PD-1 blockade therapy.
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PD-1阻断治疗背景下AML的单细胞T细胞景观和T细胞受体谱分析。
DOI：
10.1038/s41467-021-26282-z
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发表时间：
2021-10-18
影响因子：
16.6
通讯作者：
Futreal A
中科院分区：
文献类型：
--
作者：
Abbas HA;Hao D;Tomczak K;Barrodia P;Im JS;Reville PK;Alaniz Z;Wang W;Wang R;Wang F;Al-Atrash G;Takahashi K;Ning J;Ding M;Beird HC;Mathews JT;Little L;Zhang J;Basu S;Konopleva M;Marques-Piubelli ML;Solis LM;Parra ER;Lu W;Tamegnon A;Garcia-Manero G;Green MR;Sharma P;Allison JP;Kornblau SM;Rai K;Wang L;Daver N;Futreal A
与异基因干细胞移植通过T细胞活性治疗急性髓系白血病的疗效相反，检查点阻断治疗仅获得适度的反应，这可能由T细胞表型和T细胞受体（TCR）库解释。在这里，我们通过配对单细胞RNA分析和TCR库分析显示，在氮杂胞苷+纳武单抗治疗前/后，复发性/难治性急性髓性白血病患者的骨髓细胞中，疾病相关的T细胞亚群是高度异质性的，并且在基于PD-1阻断的治疗后，它们的丰度发生了变化。TCR库扩增并主要从对治疗有反应或具有稳定疾病的患者中的CD 8+细胞出现，而TCR库在治疗抗性患者中收缩。轨迹分析揭示了一个连续的CD 8 + T细胞表型，其特征在于颗粒酶B的差异表达和骨髓驻留的记忆CD 8 + T细胞亚群，其中具有干细胞样特性的群体表达颗粒酶K在应答者中富集。另一方面，染色体7/7 q缺失是AML中PD-1阻断抗性的癌症固有基因组标志物。总之，我们的研究表明，适应性T细胞可塑性和基因组改变决定了急性髓系白血病对PD-1阻断的反应。复发/难治性急性髓细胞白血病患者对PD-1检查点阻断的应答率较低且不可预测。本文作者通过单细胞RNA测序、T细胞受体谱分析和基因组分析表明，CD 8 + T细胞的表型和库以及染色体7/7 q的缺失是应答的重要决定因素。
In contrast to the curative effect of allogenic stem cell transplantation in acute myeloid leukemia via T cell activity, only modest responses are achieved with checkpoint-blockade therapy, which might be explained by T cell phenotypes and T cell receptor (TCR) repertoires. Here, we show by paired single-cell RNA analysis and TCR repertoire profiling of bone marrow cells in relapsed/refractory acute myeloid leukemia patients pre/post azacytidine+nivolumab treatment that the disease-related T cell subsets are highly heterogeneous, and their abundance changes following PD-1 blockade-based treatment. TCR repertoires expand and primarily emerge from CD8+ cells in patients responding to treatment or having a stable disease, while TCR repertoires contract in therapy-resistant patients. Trajectory analysis reveals a continuum of CD8+ T cell phenotypes, characterized by differential expression of granzyme B and a bone marrow-residing memory CD8+ T cell subset, in which a population with stem-like properties expressing granzyme K is enriched in responders. Chromosome 7/7q loss, on the other hand, is a cancer-intrinsic genomic marker of PD-1 blockade resistance in AML. In summary, our study reveals that adaptive T cell plasticity and genomic alterations determine responses to PD-1 blockade in acute myeloid leukemia. The response rate of relapsed/refractory acute myeloid leukemia patients to PD-1 checkpoint blockade is low and unpredictable. Authors here show by single cell RNA sequencing, T cell receptor profiling and genomic analysis that the phenotypes and repertoire of CD8 + T cells and loss of chromosome 7/7q are important determinants of response.
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影响因子：
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作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
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Lugli E
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82.9
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通讯作者：
Krummel MF