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Abstract：
Type I interferons (IFN-Is), secreted by hematopoietic cells, drive immune surveillance of solid tumors. However, the mechanisms of suppression of IFN-I-driven immune responses in hematopoietic malignancies including B-cell acute lymphoblastic leukemia (B-ALL) are unknown.
Using high-dimensional cytometry, we delineate the defects in IFN-I production and IFN-I-driven immune responses in high-grade primary human and mouse B-ALLs. We develop natural killer (NK) cells as therapies to counter the intrinsic suppression of IFN-I production in B-ALL.
We find that high expression of IFN-I signaling genes predicts favorable clinical outcome in patients with B-ALL, underscoring the importance of the IFN-I pathway in this malignancy. We show that human and mouse B-ALL microenvironments harbor an intrinsic defect in paracrine (plasmacytoid dendritic cell) and/or autocrine (B-cell) IFN-I production and IFN-I-driven immune responses. Reduced IFN-I production is sufficient for suppressing the immune system and promoting leukemia development in mice prone to MYC-driven B-ALL. Among anti-leukemia immune subsets, suppression of IFN-I production most markedly lowers the transcription of IL-15 and reduces NK-cell number and effector maturation in B-ALL microenvironments. Adoptive transfer of healthy NK cells significantly prolongs survival of overt ALL-bearing transgenic mice. Administration of IFN-Is to B-ALL-prone mice reduces leukemia progression and increases the frequencies of total NK and NK-cell effectors in circulation. Ex vivo treatment of malignant and non-malignant immune cells in primary mouse B-ALL microenvironments with IFN-Is fully restores proximal IFN-I signaling and partially restores IL-15 production. In B-ALL patients, the suppression of IL-15 is the most severe in difficult-to-treat subtypes with MYC overexpression. MYC overexpression promotes sensitivity of B-ALL to NK cell-mediated killing. To counter the suppressed IFN-I-induced IL-15 production in MYChigh human B-ALL, we CRISPRa-engineered a novel human NK-cell line that secretes IL-15. CRISPRa IL-15-secreting human NK cells kill high-grade human B-ALL in vitro and block leukemia progression in vivo more effectively than NK cells that do not produce IL-15.
We find that restoration of the intrinsically suppressed IFN-I production in B-ALL underlies the therapeutic efficacy of IL-15-producing NK cells and that such NK cells represent an attractive therapeutic solution for the problem of drugging MYC in high-grade B-ALL.
Using high-dimensional cytometry, we delineate the defects in IFN-I production and IFN-I-driven immune responses in high-grade primary human and mouse B-ALLs. We develop natural killer (NK) cells as therapies to counter the intrinsic suppression of IFN-I production in B-ALL.
We find that high expression of IFN-I signaling genes predicts favorable clinical outcome in patients with B-ALL, underscoring the importance of the IFN-I pathway in this malignancy. We show that human and mouse B-ALL microenvironments harbor an intrinsic defect in paracrine (plasmacytoid dendritic cell) and/or autocrine (B-cell) IFN-I production and IFN-I-driven immune responses. Reduced IFN-I production is sufficient for suppressing the immune system and promoting leukemia development in mice prone to MYC-driven B-ALL. Among anti-leukemia immune subsets, suppression of IFN-I production most markedly lowers the transcription of IL-15 and reduces NK-cell number and effector maturation in B-ALL microenvironments. Adoptive transfer of healthy NK cells significantly prolongs survival of overt ALL-bearing transgenic mice. Administration of IFN-Is to B-ALL-prone mice reduces leukemia progression and increases the frequencies of total NK and NK-cell effectors in circulation. Ex vivo treatment of malignant and non-malignant immune cells in primary mouse B-ALL microenvironments with IFN-Is fully restores proximal IFN-I signaling and partially restores IL-15 production. In B-ALL patients, the suppression of IL-15 is the most severe in difficult-to-treat subtypes with MYC overexpression. MYC overexpression promotes sensitivity of B-ALL to NK cell-mediated killing. To counter the suppressed IFN-I-induced IL-15 production in MYChigh human B-ALL, we CRISPRa-engineered a novel human NK-cell line that secretes IL-15. CRISPRa IL-15-secreting human NK cells kill high-grade human B-ALL in vitro and block leukemia progression in vivo more effectively than NK cells that do not produce IL-15.
We find that restoration of the intrinsically suppressed IFN-I production in B-ALL underlies the therapeutic efficacy of IL-15-producing NK cells and that such NK cells represent an attractive therapeutic solution for the problem of drugging MYC in high-grade B-ALL.
摘要：
背景：I型干扰素（IFN-Is），由造血细胞分泌，驱动实体瘤的免疫监视。然而,在造血系统恶性肿瘤包括B细胞急性淋巴细胞白血病(B-ALL)中,IFN-I驱动的免疫应答的抑制机制尚不清楚.
方法：使用高维细胞计数，我们描述了高级别原发性人类和小鼠B-ALL中IFN-I产生和IFN-I驱动的免疫应答的缺陷。我们开发了自然杀伤（NK）细胞作为治疗来对抗B-ALL中IFN-I产生的内在抑制。
结果：我们发现IFN-I信号基因的高表达预示着B-ALL患者的良好临床结局，强调IFN-I途径在这种恶性肿瘤中的重要性。我们表明，人和小鼠B-ALL微环境在旁分泌（浆细胞样树突状细胞）和/或自分泌（B细胞）IFN-I产生和IFN-I驱动的免疫反应中存在内在缺陷。减少的IFN-I产生足以抑制免疫系统并促进易于MYC驱动的B-ALL的小鼠中的白血病发展。在抗白血病免疫亚群中，抑制IFN-I的产生最显着降低IL-15的转录并减少B-ALL微环境中的NK细胞数量和效应物成熟。健康NK细胞的过继转移可显着延长带有ALL的转基因小鼠的存活。对B-ALL易感小鼠施用IFN-Is减少白血病进展并增加循环中总NK和NK细胞效应物的频率。用IFN-Is对原代小鼠B-ALL微环境中的恶性和非恶性免疫细胞的离体治疗完全恢复了近端IFN-I信号传导并部分恢复了IL-15的产生。在B-ALL患者中，IL-15的抑制在MYC过表达的难以治疗的亚型中是最严重的。MYC过表达促进B-ALL对NK细胞介导的杀伤的敏感性。为了对抗MYCHH人B-ALL中IFN-I诱导的IL-15产生的抑制，我们CRISPRa改造了一种分泌IL-15的新型人类NK细胞系。分泌CRISPRaIL-15的人NK细胞比不产生IL-15的NK细胞更有效地在体外杀死高级人B-ALL并在体内阻断白血病进展。
结论：我们发现，在B-ALL中恢复固有抑制的IFN-I产生是产生IL-15的NK细胞的治疗功效的基础，并且这种NK细胞代表了在高级B-ALL中对MYC进行药物治疗的有吸引力的治疗解决方案。
方法：使用高维细胞计数，我们描述了高级别原发性人类和小鼠B-ALL中IFN-I产生和IFN-I驱动的免疫应答的缺陷。我们开发了自然杀伤（NK）细胞作为治疗来对抗B-ALL中IFN-I产生的内在抑制。
结果：我们发现IFN-I信号基因的高表达预示着B-ALL患者的良好临床结局，强调IFN-I途径在这种恶性肿瘤中的重要性。我们表明，人和小鼠B-ALL微环境在旁分泌（浆细胞样树突状细胞）和/或自分泌（B细胞）IFN-I产生和IFN-I驱动的免疫反应中存在内在缺陷。减少的IFN-I产生足以抑制免疫系统并促进易于MYC驱动的B-ALL的小鼠中的白血病发展。在抗白血病免疫亚群中，抑制IFN-I的产生最显着降低IL-15的转录并减少B-ALL微环境中的NK细胞数量和效应物成熟。健康NK细胞的过继转移可显着延长带有ALL的转基因小鼠的存活。对B-ALL易感小鼠施用IFN-Is减少白血病进展并增加循环中总NK和NK细胞效应物的频率。用IFN-Is对原代小鼠B-ALL微环境中的恶性和非恶性免疫细胞的离体治疗完全恢复了近端IFN-I信号传导并部分恢复了IL-15的产生。在B-ALL患者中，IL-15的抑制在MYC过表达的难以治疗的亚型中是最严重的。MYC过表达促进B-ALL对NK细胞介导的杀伤的敏感性。为了对抗MYCHH人B-ALL中IFN-I诱导的IL-15产生的抑制，我们CRISPRa改造了一种分泌IL-15的新型人类NK细胞系。分泌CRISPRaIL-15的人NK细胞比不产生IL-15的NK细胞更有效地在体外杀死高级人B-ALL并在体内阻断白血病进展。
结论：我们发现，在B-ALL中恢复固有抑制的IFN-I产生是产生IL-15的NK细胞的治疗功效的基础，并且这种NK细胞代表了在高级B-ALL中对MYC进行药物治疗的有吸引力的治疗解决方案。
