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Macrophage Syk-PI3Kγ inhibits anti-tumor immunity: SRX3207, a novel dual Syk-PI3K inhibitory chemotype relieves tumor immunosuppression.

巨噬细胞 syk-pi3k γ 抑制抗肿瘤免疫: SRX3207,一种新型双 Syk-PI3K 抑制性趋化型缓解肿瘤免疫抑制。

  • 影响因子:5.25
  • DOI:10.1158/1535-7163.MCT-19-0947
  • 作者列表:"Joshi S","Liu KX","Zulcic M","Singh AR","Skola D","Glass CK","Sanders PD","Sharabi AB","Pham TV","Tamayo P","Shiang D","Dinh HQ","Hedrick CC","Morales GA","Garlich JR","Durden DL
  • 发表时间:2020-01-23
Abstract

: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 a macrophage Syk-PI3K axis drives polarization of immunosuppressive MΦs which establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacological inhibition of Syk and/or PI3Kγ in MΦs promotes a pro-inflammatory MΦphenotype, 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 (BMDMs) 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.

摘要

巨噬细胞 (m φ) 在肿瘤生长、免疫抑制和抑制癌症的适应性免疫反应中起关键作用。因此,靶向促进肿瘤免疫抑制的 m Φ s 中的信号通路将提供治疗益处。Pi3k γ 最近被我们和其他小组确定为一个新的免疫肿瘤靶点。在此,我们报道了巨噬细胞 Syk-PI3K 轴驱动免疫抑制 m Φ s 极化,在体内同基因肿瘤模型中建立免疫抑制肿瘤微环境。M Φ s 中 Syk 和/或 pi3k γ 的遗传或药理学抑制促进促炎性 m Φ 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。使用骨髓来源的巨噬细胞 (BMDMs) 的测序 (ATAC-seq) 分析检测转座酶可接近的染色质表明抑制 Syk 激酶促进 SykMC-KO BMDMs 中 NF-κ b 基序的激活和结合,从而刺激 m Φ s 中的免疫刺激转录编程以抑制肿瘤生长。最后,我们在计算机模拟中开发了 “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。这种化学类型在多种肿瘤模型中表现出疗效,代表了一种激活抗肿瘤免疫的新型组合方法。

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影响因子:5.25
发表时间:2020-01-23
DOI:10.1158/1535-7163.MCT-19-0947
作者列表:["Joshi S","Liu KX","Zulcic M","Singh AR","Skola D","Glass CK","Sanders PD","Sharabi AB","Pham TV","Tamayo P","Shiang D","Dinh HQ","Hedrick CC","Morales GA","Garlich JR","Durden DL"]

METHODS::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 a macrophage Syk-PI3K axis drives polarization of immunosuppressive MΦs which establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacological inhibition of Syk and/or PI3Kγ in MΦs promotes a pro-inflammatory MΦphenotype, 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 (BMDMs) 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.

关键词: 暂无
翻译标题与摘要 下载文献
影响因子:12.19
发表时间:2020-01-23
来源期刊:Nature communications
DOI:10.1038/s41467-020-14332-x
作者列表:["Fu S","He K","Tian C","Sun H","Zhu C","Bai S","Liu J","Wu Q","Xie D","Yue T","Shen Z","Dai Q","Yu X","Zhu S","Liu G","Zhou R","Duan S","Tian Z","Xu T","Wang H","Bai L"]

METHODS::Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis.

关键词: 暂无
翻译标题与摘要 下载文献
影响因子:8.58
发表时间:2020-01-17
DOI:10.1158/2326-6066.CIR-19-0517
作者列表:["Maruoka Y","Furusawa A","Okada R","Inagaki F","Fujimura D","Wakiyama H","Kato T","Nagaya T","Choyke PL","Kobayashi H"]

METHODS::Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed and selective cancer treatment that induces necrotic and immunogenic cell death and utilizes a monoclonal antibody conjugated to a photo-absorber dye, IR700DX, activated by NIR light. Although CD44 is surface cancer marker associated with drug resistance, anti-CD44-IR700 NIR-PIT results in inhibited cell growth and prolonged survival in multiple tumor types. Meanwhile, anti-CD25-IR700-targeted NIR-PIT has been reported to achieve selective and local depletion of FOXP3+CD25+CD4+ regulatory T cells (Tregs), which are primary immunosuppressive cells in the tumor microenvironment (TME), resulting in activation of local antitumor immunity. Combined NIR-PIT with CD44- and CD25-targeted agents has the potential to directly eliminate tumor cells and also amplify the immune response by removing FOXP3+CD25+CD4+ Tregs from the TME. We investigated the difference in therapeutic effects of CD44-targeted NIR-PIT alone, CD25-targeted NIR-PIT alone, and the combination of CD44- and CD25-targeted NIR-PIT in several syngeneic tumor models, including MC38-luc, LL/2, and MOC1. The combined NIR-PIT showed significant tumor growth inhibition and prolonged survival compared with CD44-targeted NIR-PIT alone in all tumor models and showed prolonged survival compared with CD25-targeted NIR-PIT alone in MC38-luc and LL/2 tumors. Combined CD44/CD25 NIR-PIT also resulted in some complete remissions, whereas this was not achieved with either type of NIR-PIT alone. Therefore, combined NIR-PIT simultaneously targeting cancer antigens and immunosuppressive cells in the TME may be more effective than either type of NIR-PIT alone and may have potential to induce prolonged immune responses in treated tumors.

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