Epigenetic modulation of neuroblastoma enhances T cell and NK cell immunogenicity by inducing a tumor-cell lineage switch.
Epigenetic modulation of neuroblastoma enhances T cell and NK cell immunogenicity by inducing a tumor-cell lineage switch.
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DOI：
10.1136/jitc-2022-005002
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发表时间：
2022-12
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
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作者：
高危神经母细胞瘤（HR-NBL）的免疫治疗由于HR-NBL广泛的免疫调节能力引起的（适应性）免疫参与不足而无法充分发挥其潜力。我们旨在解决神经母细胞瘤（NBL）中最显著的免疫调节过程之一，缺乏主要组织相容性复合物I类（MHC-I）表面表达，这是一个极大限制细胞毒性T细胞参与的过程。我们和其他人先前已经表明，MHC-I的表达可以诱导由精氨酸驱动的免疫调节。在这里，我们的目的是确定可耐受的药理学再利用的策略，上调MHC-I的表达，从而增强T细胞免疫原性NBL。使用针对贴壁细胞优化的高通量流式细胞术分析，筛选药物再利用文库以鉴定增强NBL细胞中MHC-I表面表达的化合物。阳性命中的影响在一组NBL细胞系和患者来源的类器官中得到了证实。将化合物处理的NBL细胞系和类器官与优先表达的黑色素瘤抗原（PRAME）反应性肿瘤特异性T细胞和健康供体自然杀伤（NK）细胞共培养，以确定对T细胞和NK细胞细胞毒性的体外作用。组蛋白脱乙酰酶抑制剂（HDACi）的额外免疫调节作用通过经处理的类器官的转录组和翻译组分析来鉴定。药物库筛选揭示了MHC-I通过凋亡抑制剂抑制剂（IAPi）-和HDACi药物类的上调。由于NBL中核因子κ B（NFκB）通路活性的抑制，IAPi的作用有限，而HDACi的MHC-I调节作用广泛适用于一组NBL细胞系和患者来源的类器官。用HDACi恩替诺特预处理NBL细胞增强了肿瘤特异性T细胞在体外对NBL的细胞毒性能力，这与调节T细胞细胞毒性的其他参与者（例如，TAP 1/2和免疫蛋白酶体亚基）的表达增加一致。此外，在NK细胞细胞毒性中重要的云母和MICB也通过恩替司他暴露而增加。有趣的是，这种免疫原性的增加伴随着向更间充质的NBL细胞谱系的转变。本研究表明，联合（免疫）治疗与HDACi增强HR-NBL患者T细胞驱动和NK细胞驱动的免疫应答的潜力。
Immunotherapy in high-risk neuroblastoma (HR-NBL) does not live up to its full potential due to inadequate (adaptive) immune engagement caused by the extensive immunomodulatory capacity of HR-NBL. We aimed to tackle one of the most notable immunomodulatory processes in neuroblastoma (NBL), absence of major histocompatibility complex class I (MHC-I) surface expression, a process greatly limiting cytotoxic T cell engagement. We and others have previously shown that MHC-I expression can be induced by cytokine-driven immune modulation. Here, we aimed to identify tolerable pharmacological repurposing strategies to upregulate MHC-I expression and therewith enhance T cell immunogenicity in NBL. Drug repurposing libraries were screened to identify compounds enhancing MHC-I surface expression in NBL cells using high-throughput flow cytometry analyses optimized for adherent cells. The effect of positive hits was confirmed in a panel of NBL cell lines and patient-derived organoids. Compound-treated NBL cell lines and organoids were cocultured with preferentially expressed antigen of melanoma (PRAME)-reactive tumor-specific T cells and healthy-donor natural killer (NK) cells to determine the in vitro effect on T cell and NK cell cytotoxicity. Additional immunomodulatory effects of histone deacetylase inhibitors (HDACi) were identified by transcriptome and translatome analysis of treated organoids. Drug library screening revealed MHC-I upregulation by inhibitor of apoptosis inhibitor (IAPi)- and HDACi drug classes. The effect of IAPi was limited due to repression of nuclear factor kappa B (NFκB) pathway activity in NBL, while the MHC-I-modulating effect of HDACi was widely translatable to a panel of NBL cell lines and patient-derived organoids. Pretreatment of NBL cells with the HDACi entinostat enhanced the cytotoxic capacity of tumor-specific T cells against NBL in vitro, which coincided with increased expression of additional players regulating T cell cytotoxicity (eg, TAP1/2 and immunoproteasome subunits). Moreover, MICA and MICB, important in NK cell cytotoxicity, were also increased by entinostat exposure. Intriguingly, this increase in immunogenicity was accompanied by a shift toward a more mesenchymal NBL cell lineage. This study indicates the potential of combining (immuno)therapy with HDACi to enhance both T cell-driven and NKcell-driven immune responses in patients with HR-NBL.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
5.8
作者：
Briere, David;Sudhakar, Niranjan;Christensen, James G.
通讯作者：
Christensen, James G.
影响因子：
5.4
作者：
Dull, T;Zufferey, R;Naldini, L
通讯作者：
Naldini, L
影响因子：
16.6
作者：
Beug ST;Beauregard CE;Healy C;Sanda T;St-Jean M;Chabot J;Walker DE;Mohan A;Earl N;Lun X;Senger DL;Robbins SM;Staeheli P;Forsyth PA;Alain T;LaCasse EC;Korneluk RG
通讯作者：
Korneluk RG
DOI：
10.1016/j.omtm.2021.03.015
发表时间：
2021-06-11
期刊：
Molecular therapy. Methods & clinical development
影响因子：
--
作者：
Lo Presti V;Cornel AM;Plantinga M;Dünnebach E;Kuball J;Boelens JJ;Nierkens S;van Til NP
通讯作者：
van Til NP