Systemic but not MDSC-specific IRF4 deficiency promotes an immunosuppressed tumor microenvironment in a murine pancreatic cancer model.
Systemic but not MDSC-specific IRF4 deficiency promotes an immunosuppressed tumor microenvironment in a murine pancreatic cancer model.
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DOI：
10.1007/s00262-020-02605-9
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
König LM
中科院分区：
文献类型：
--
作者：
Metzger P;Kirchleitner SV;Boehmer DFR;Hörth C;Eisele A;Ormanns S;Gunzer M;Lech M;Lauber K;Endres S;Duewell P;Schnurr M;König LM
胰腺导管腺癌的特点是具有强大的免疫抑制网络和密集的髓系细胞，包括髓系细胞来源的抑制细胞(MDSC)。MDSC有两个不同的群体：中性粒细胞MDSC(PMN-MDSC)和单核细胞MDSC(M-MDSC)。多种因素影响MDSC的发育和功能，其中包括转录因子干扰素调节因子4(IRF4)。在这里，我们发现IRF4缺乏加速了肿瘤的生长并降低了存活率，同时伴有致密的PMN-MDSC和CD8+T细胞的数量减少。由于IRF4已被描述为调节髓系细胞的发育和功能，尤其是PMN-MDSC，我们使用具有Ly6G或LysM敲入等位基因表达Cre重组酶和Irf4flx的MDSC特异性IRF4基因敲除小鼠来分析其作用。在GM-CSF驱动的骨髓培养中，IRF4缺乏增加了具有较强T细胞抑制能力的MDSC样细胞的频率。髓系(LysM)特异性缺失IRF4导致荷瘤小鼠肿瘤重量增加和脾M-MDSC适度扩张。然而，PMN细胞(Ly6G)特异性缺失IRF4并没有影响肿瘤的进展或体内MDSC的聚集，这与我们的发现一致，即IRF4在PMN-MDSC中不表达。本研究证实了IRF4在胰腺癌免疫抑制肿瘤微环境形成中的关键作用，这种作用不依赖于PMN-MDSC中IRF4的表达。本文的在线版本(10.1007/s00262-020-02605-9)包含补充材料，授权用户可以使用。
Pancreatic ductal adenocarcinoma is characterized by a strong immunosuppressive network with a dense infiltration of myeloid cells including myeloid-derived suppressor cells (MDSC). Two distinct populations of MDSC have been defined: polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC). Several factors influence the development and function of MDSC including the transcription factor interferon regulatory factor 4 (IRF4). Here, we show that IRF4 deficiency accelerates tumor growth and reduces survival, accompanied with a dense tumor infiltration with PMN-MDSC and reduced numbers of CD8+ T cells. As IRF4 has been described to modulate myeloid cell development and function, particularly of PMN-MDSC, we analyzed its role using MDSC-specific IRF4 knockout mice with the Ly6G or LysM knock-in allele expressing Cre recombinase and Irf4flox. In GM-CSF-driven bone marrow cultures, IRF4 deficiency increased the frequency of MDSC-like cells with a strong T cell suppressive capacity. Myeloid (LysM)-specific depletion of IRF4 led to increased tumor weight and a moderate splenic M-MDSC expansion in tumor-bearing mice. PMN cell (Ly6G)-specific depletion of IRF4, however, did not influence tumor progression or MDSC accumulation in vivo in accordance with our finding that IRF4 is not expressed in PMN-MDSC. This study demonstrates a critical role of IRF4 in the generation of an immunosuppressive tumor microenvironment in pancreatic cancer, which is independent of IRF4 expression in PMN-MDSC. The online version of this article (10.1007/s00262-020-02605-9) contains supplementary material, which is available to authorized users.
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影响因子：
32.4
作者：
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