通过抑制髓系衍生抑制细胞中的 PI3K-gamma 信号,防止手术引起的免疫抑制和转移。

Leonard Angka, Gayashan Tennakoon, David P Cook, Andre B Martel, Marisa R Market, Christiano Tanese de Souza, Emma Cummins, Ismael Samudio, Natasha Kekre, Michele Ardolino, Barbara Vanderhyden, Michael A Kennedy, Rebecca C Auer
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引用次数: 0

摘要

髓系衍生抑制细胞(MDSCs)在术后占主导地位,并在术后介导抑制自然杀伤细胞(NK)和促进癌症转移。然而,它们的功能特点及其对术后细胞免疫的影响尚未得到全面研究。在这里,我们通过多色流式细胞术、单细胞 RNA 测序和体内外 NK 细胞抑制功能测试,描述了手术诱导(sx)MDSCs 的扩增特征。然后,我们利用我们的sx-MDSC:NK细胞抑制实验筛选了一个小分子库,以确定能抑制sx-MDSCs的化合物。这些研究提供的证据表明,PI3K-γ 信号在 sx-MDSCs 中上调,使用 PI3K-γ 特异性抑制剂阻断 PI3K-γ 信号可减轻人和小鼠的 NK 细胞抑制,并减少小鼠模型的术后转移。sx-MDSCs中上调的PI3K-γ是一种潜在的途径,可用于术后靶向治疗。
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Preventing surgery induced immune suppression and metastases by inhibiting PI3K-gamma signalling in Myeloid-Derived Suppressor Cells.
Myeloid derived suppressor cells (MDSCs) have a dominating presence in the postoperative period and mediate the suppression of Natural Killer (NK) cells and promotion of cancer metastases after surgery. However, their functional characteristics and effect on cellular immunity after surgery have not been comprehensively investigated. Here, we characterize the expansion of surgery-induced (sx) MDSCs via multi-colour flow cytometry, single-cell RNA sequencing, and functional ex vivo NK cell suppression assays. We then screened a small molecule library using our sx-MDSC:NK cell suppression assay to identify compounds that could inhibit sx-MDSCs. These studies provide evidence that PI3K-γ signalling is upregulated in sx-MDSCs and blockade with PI3K-γ specific inhibitors attenuates NK cell suppression in humans and mice and reduces postoperative metastases in murine models. Upregulated PI3K-γ in sx-MDSCs is a potential pathway amenable to therapeutic targeting in the postoperative period.
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