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CD20 耐药性非霍奇金淋巴瘤中 CD19-CAR 自然杀伤细胞治疗的转录组和分泌反应的相互作用动力学。

Interaction kinetics with transcriptomic and secretory responses of CD19-CAR natural killer-cell therapy in CD20 resistant non-hodgkin lymphoma.

机构信息

Division of Blood Disorders, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.

Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.

出版信息

Leukemia. 2020 May;34(5):1291-1304. doi: 10.1038/s41375-019-0663-x. Epub 2019 Nov 26.

DOI:10.1038/s41375-019-0663-x
PMID:31772298
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7196029/
Abstract

We investigated the cytolytic and mechanistic activity of anti-CD19 chimeric antigen receptor natural killer (CD19.CAR.NK92) therapy in lymphoma cell lines (diffuse large B-cell, follicular, and Burkitt lymphoma), including rituximab- and obinutuzumab-resistant cells, patient-derived cells, and a human xenograft model. CD19.CAR.NK92 therapy significantly increased cytolytic activity at E:T ratios (1:1-10:1) via LDH release and prominent induction of apoptosis in all cell lines, including in anti-CD20 resistant lymphoma cells. The kinetics of CD19.CAR.NK92 cell death measured via droplet-based single cell microfluidics analysis showed that most lymphoma cells were killed by single contact, with anti-CD20 resistant cell lines requiring significantly longer contact duration with NK cells. In addition, systems biology transcriptomic analyses of flow-sorted lymphoma cells co-cultured with CD19.CAR.NK92 revealed conserved activation of IFNγ signaling, execution of apoptosis, ligand binding, and immunoregulatory and chemokine signaling pathways. Furthermore, a 92-plex cytokine panel analysis showed increased secretion of granzymes, increased secretion of FASL, CCL3, and IL10 in anti-CD20 resistant SUDHL4 cells with induction of genes relevant to mTOR and G2/M checkpoint activation, which were noted in all anti-CD20 resistant cells co-cultured with CD19.CAR.NK92 cells. Collectively, CD19.CAR.NK92 was associated with potent anti-lymphoma activity across a host of sensitive and resistant lymphoma cells that involved distinct immuno-biologic mechanisms of cell death.

摘要

我们研究了抗 CD19 嵌合抗原受体自然杀伤（CD19.CAR.NK92）治疗在淋巴瘤细胞系（弥漫性大 B 细胞、滤泡性和伯基特淋巴瘤）中的细胞溶解和作用机制活性，包括利妥昔单抗和奥滨尤妥珠单抗耐药细胞、患者来源的细胞和人异种移植模型。CD19.CAR.NK92 治疗通过 LDH 释放显著增加了在 E:T 比（1:1-10:1）时的细胞溶解活性，并在所有细胞系中诱导明显的凋亡，包括在抗 CD20 耐药淋巴瘤细胞中。通过基于液滴的单细胞微流控分析测量的 CD19.CAR.NK92 细胞死亡动力学表明，大多数淋巴瘤细胞通过单次接触被杀死，而抗 CD20 耐药细胞系需要与 NK 细胞更长时间的接触。此外，与 CD19.CAR.NK92 共培养的流式分选淋巴瘤细胞的系统生物学转录组学分析显示 IFNγ 信号的保守激活、凋亡的执行、配体结合以及免疫调节和趋化因子信号通路。此外，92 plex 细胞因子面板分析显示，在 SUDHL4 抗 CD20 耐药细胞中，颗粒酶的分泌增加，FASL、CCL3 和 IL10 的分泌增加，同时诱导与 mTOR 和 G2/M 检查点激活相关的基因，这在所有与 CD19.CAR.NK92 细胞共培养的抗 CD20 耐药细胞中都有发现。总之，CD19.CAR.NK92 与多种敏感和耐药淋巴瘤细胞的强大抗淋巴瘤活性相关，涉及到不同的细胞死亡免疫生物学机制。

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