利用细胞外ATP抑制CD39增强抗肿瘤免疫。

IF 3.4 3区 医学 Q2 IMMUNOLOGY
Ke Jin, Rebecca Fuchs, Julie Clor, Jenna L Pappalardo, Kaustubh Parashar, Soonweng Cho, Nigel P C Walker, Matthew J Walters, Ester Fernandez-Salas, Christine E Bowman
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引用次数: 0

摘要

CD39(由ENTPD1编码)已成为肿瘤治疗的靶点。抑制CD39保存细胞外三磷酸腺苷(eATP),减少细胞外腺苷(eADO)的形成,从而增加eATP/eADO的比值,促进免疫刺激。在癌症基因组图谱(TCGA)中,所有实体肿瘤中eATPases的RNA表达谱表明,ENTPD1的表达最为广泛。这些eATPases的酶学表征表明,CD39在pH值为6.8时具有最大的催化活性,这是肿瘤微环境中普遍存在的温和酸性pH值,这表明CD39是保存eATP的理想治疗靶点。在MC38肿瘤模型中,抑制CD39与抗pd -1治疗联合可增强骨髓细胞活化和肿瘤控制。为了更好地理解如何将小鼠的结果转化为化疗是标准护理的人类环境,开发了人类单核细胞来源的树突状细胞/T细胞/癌细胞系共培养系统。CD39抑制导致IL-2、颗粒酶B和IFNγ的产生增加,表明化疗诱导的eATP产生足以促进髓细胞活化,从而增强T细胞功能。使用共培养系统,我们生成了第一个在原代人髓细胞上开发的转录eATP特征,并将其应用于现实世界的数据集,说明了可以在人类肿瘤中测量的对eATP的反应。这些研究为CD39抑制通过增强eap驱动的T细胞的髓细胞活化在各种肿瘤环境和eap生成模式中促进抗肿瘤免疫提供了机制基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Harnessing CD39 inhibition to boost antitumor immunity with extracellular ATP.

CD39 (encoded by ENTPD1) has emerged as a target for oncologic therapies. Inhibition of CD39 preserves extracellular adenosine triphosphate (eATP) and decreases extracellular adenosine (eADO) formation, thereby increasing the eATP/eADO ratio and promoting immune stimulation. RNA expression profiling of eATPases across all solid tumors in The Cancer Genome Atlas (TCGA) demonstrates that ENTPD1 has the most widespread expression. Enzymatic characterization of these eATPases shows CD39 to have the greatest catalytic activity at pH 6.8, the prevailing mildly acidic pH of the tumor microenvironment, highlighting CD39 as an ideal therapeutic target of choice for eATP preservation. In an MC38 tumor model, inhibition of CD39 led to enhanced myeloid cell activation and tumor control when combined with anti-PD-1 therapy. To better understand how the murine results would translate to a human setting in which chemotherapy is the standard of care, a human monocyte-derived dendritic cell/T cell/carcinoma cell line coculture system was developed. CD39 inhibition led to greater production of IL-2, granzyme B, and IFNγ, demonstrating that chemotherapy-induced eATP generation is sufficient to promote myeloid cell activation, resulting in enhanced T cell function. Using the coculture system, we generated the first transcriptional eATP signature developed on primary human myeloid cells and applied it to real-world datasets, illustrating a response to eATP that can be measured in human tumors. These studies provide a mechanistic rationale for CD39 inhibition to promote antitumor immunity via the enhancement of eATP-driven myeloid cell activation of T cells across a variety of tumor settings and eATP-generative modalities.

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来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
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