PI3Kγ Activates Integrin α(4) and Promotes Immune Suppressive Myeloid Cell Polarization during Tumor Progression.
PI3Kγ Activates Integrin α(4) and Promotes Immune Suppressive Myeloid Cell Polarization during Tumor Progression.
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DOI：
10.1158/2326-6066.cir-17-0143
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发表时间：
2017-11
影响因子：
10.1
通讯作者：
Varner JA
中科院分区：
文献类型：
--
作者：
Foubert P;Kaneda MM;Varner JA
免疫抑制性骨髓源性抑制细胞（MDSC）和肿瘤相关巨噬细胞（TAM）在肿瘤中积聚，它们抑制T细胞介导的抗肿瘤免疫应答并促进肿瘤进展。髓样细胞PI 3 K γ通过促进整合素α4依赖性MDSC向肿瘤的募集以及通过刺激MDSC和TAM的免疫抑制极化在调节肿瘤免疫抑制中起关键作用。在这里，我们发现整合素α4促进PI 3 K γ下游MDSC和TAM的免疫抑制极化，从而抑制抗肿瘤免疫。PI 3 K γ或整联蛋白α4的遗传或药理学抑制阻断了MDSC向肿瘤的募集，也抑制了免疫抑制性髓样细胞极化，从而显著降低了肿瘤内IL-10的表达并增加了IL-12和IFNγ的表达。抑制肿瘤内的PI 3 K γ或整合素α4刺激树突状细胞和CD 8 + T细胞的募集和成熟，以及体内肿瘤细胞的细胞毒性，从而抑制肿瘤生长。由于PI 3 K γ或整联蛋白α4的阻断可防止MDSC的积聚并减少刺激肿瘤免疫逃逸的免疫抑制因子的骨髓细胞表达，因此这些结果表明PI 3 K γ和整联蛋白α4是设计新型癌症治疗剂的有价值的靶标。
Immunosuppressive myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) accumulate in tumors where they inhibit T cell-mediated anti-tumor immune responses and promote tumor progression. Myeloid cell PI3Kγ plays a key role in regulating tumor immune suppression by promoting integrin α4-dependent MDSC recruitment to tumors and by stimulating immune suppressive polarization of MDSCs and TAMs. Here we show that integrin α4 promotes immune suppressive polarization of MDSCs and TAMs downstream of PI3Kγ, thereby inhibiting anti-tumor immunity. Genetic or pharmacological suppression of either PI3Kγ or integrin α4 blocked MDSC recruitment to tumors and also inhibited immune suppressive myeloid cell polarization, thereby significantly reducing expression of IL-10 and increasing expression of IL-12 and IFNγ within tumors. Inhibition of PI3Kγ or integrin α4 within tumors stimulated dendritic cell and CD8+ T cell recruitment and maturation, as well as tumor cell cytotoxicity in vivo, thereby inhibiting tumor growth. As blockade of PI3Kγ or integrin α4 prevents accumulation of MDSC and reduces myeloid cell expression of immunosuppressive factors that stimulate tumor immune escape, these results indicate that PI3Kγ and integrin α4 are valuable targets for the design of novel cancer therapeutics.