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Macrophage Syk-PI3Kγ inhibits anti-tumor immunity: SRX3207, a novel dual Syk-PI3K inhibitory chemotype relieves tumor immunosuppression
Molecular Cancer Therapeutics ( IF 5.7 ) Pub Date : 2020-01-23 , DOI: 10.1158/1535-7163.mct-19-0947
Shweta Joshi 1 , Kevin X Liu 1 , Muamera Zulcic 1 , Alok R Singh 1 , Dylan Skola 2 , Christopher K Glass 2 , P Dominick Sanders 3 , Andrew B Sharabi 3 , Timothy V Pham 1, 4 , Pablo Tamayo 4 , Daniel Shiang 1 , Huy Q Dinh 5 , Catherine C Hedrick 5 , Guillermo A Morales 6 , Joseph R Garlich 6 , Donald L Durden 1, 6
Affiliation  

Macrophages (MΦ) play a critical role in tumor growth, immunosuppression, and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in MΦs that promote tumor immunosuppression will provide therapeutic benefit. PI3Kγ has been recently established by our group and others as a novel immuno-oncology target. Herein, we report that an MΦ Syk–PI3K axis drives polarization of immunosuppressive MΦs that establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacologic inhibition of Syk and/or PI3Kγ in MΦs promotes a proinflammatory MΦ phenotype, restores CD8+ T-cell activity, destabilizes HIF under hypoxia, and stimulates an antitumor immune response. Assay for transposase-accessible Chromatin using Sequencing (ATAC-seq) analyses on the bone marrow–derived macrophages (BMDM) show that inhibition of Syk kinase promotes activation and binding of NF-κB motif in SykMC-KO BMDMs, thus stimulating immunostimulatory transcriptional programming in MΦs to suppress tumor growth. Finally, we have developed in silico the “first-in-class” dual Syk/PI3K inhibitor, SRX3207, for the combinatorial inhibition of Syk and PI3K in one small molecule. This chemotype demonstrates efficacy in multiple tumor models and represents a novel combinatorial approach to activate antitumor immunity.

中文翻译:

巨噬细胞 Syk-PI3Kγ 抑制抗肿瘤免疫:SRX3207,一种新型双重 Syk-PI3K 抑制化学型可缓解肿瘤免疫抑制

巨噬细胞 (MΦ) 在肿瘤生长、免疫抑制和抑制癌症中的适应性免疫反应中起着关键作用。因此,靶向 MΦ 中促进肿瘤免疫抑制的信号通路将提供治疗益处。PI3Kγ 最近已被我们的团队和其他人确立为一种新的免疫肿瘤学靶点。在此,我们报告了 MΦ Syk-PI3K 轴驱动免疫抑制性 MΦs 的极化,从而在体内同基因肿瘤模型中建立了免疫抑制性肿瘤微环境。MΦ 中 Syk 和/或 PI3Kγ 的遗传或药理学抑制可促进促炎 MΦ 表型,恢复 CD8+ T 细胞活性,在缺氧条件下使 HIF 不稳定,并刺激抗肿瘤免疫反应。使用测序 (ATAC-seq) 对骨髓衍生巨噬细胞 (BMDM) 进行转座酶可及染色质分析表明,抑制 Syk 激酶可促进 SykMC-KO BMDM 中 NF-κB 基序的激活和结合,从而刺激免疫刺激性转录编程在 MΦs 中抑制肿瘤生长。最后,我们在计算机上开发了“一流的”双重 Syk/PI3K 抑制剂 SRX3207,用于在一个小分子中组合抑制 Syk 和 PI3K。这种化学型在多种肿瘤模型中表现出有效性,代表了一种激活抗肿瘤免疫的新组合方法。我们在计算机上开发了“一流的”双重 Syk/PI3K 抑制剂 SRX3207,用于在一个小分子中组合抑制 Syk 和 PI3K。这种化学型在多种肿瘤模型中表现出有效性,代表了一种激活抗肿瘤免疫的新组合方法。我们在计算机上开发了“一流的”双重 Syk/PI3K 抑制剂 SRX3207,用于在一个小分子中组合抑制 Syk 和 PI3K。这种化学型在多种肿瘤模型中表现出有效性,代表了一种激活抗肿瘤免疫的新组合方法。
更新日期:2020-01-23
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