Gato-Cañas Maria, Martinez de Morentin Xabier, Blanco-Luquin Idoia, Fernandez-Irigoyen Joaquin, Zudaire Isabel, Liechtenstein Therese, Arasanz Hugo, Lozano Teresa, Casares Noelia, Chaikuad Apirat, Knapp Stefan, Guerrero-Setas David, Escors David, Kochan Grazyna, Santamaría Enrique
Immunomodulation Group, Navarrabiomed-FMS, IdiSNA, Pamplona, Spain.
Immunomodulation Group, Division of Infection and Immunity, University College, London, UK.
Oncotarget. 2015 Sep 29;6(29):27160-75. doi: 10.18632/oncotarget.4746.
Myeloid-derived suppressor cells (MDSCs) differentiate from bone marrow precursors, expand in cancer-bearing hosts and accelerate tumor progression. MDSCs have become attractive therapeutic targets, as their elimination strongly enhances anti-neoplastic treatments. Here, immature myeloid dendritic cells (DCs), MDSCs modeling tumor-infiltrating subsets or modeling non-cancerous (NC)-MDSCs were compared by in-depth quantitative proteomics. We found that neoplastic MDSCs differentially expressed a core of kinases which controlled lineage-specific (PI3K-AKT and SRC kinases) and cancer-induced (ERK and PKC kinases) protein interaction networks (interactomes). These kinases contributed to some extent to myeloid differentiation. However, only AKT and ERK specifically drove MDSC differentiation from myeloid precursors. Interfering with AKT and ERK with selective small molecule inhibitors or shRNAs selectively hampered MDSC differentiation and viability. Thus, we provide compelling evidence that MDSCs constitute a distinct myeloid lineage distinguished by a "kinase signature" and well-defined interactomes. Our results define new opportunities for the development of anti-cancer treatments targeting these tumor-promoting immune cells.
髓系来源的抑制细胞（MDSCs）由骨髓前体细胞分化而来，在荷瘤宿主体内扩增并加速肿瘤进展。MDSCs已成为有吸引力的治疗靶点，因为消除它们能显著增强抗肿瘤治疗效果。在此，通过深度定量蛋白质组学比较了未成熟髓样树突状细胞（DCs）、模拟肿瘤浸润亚群的MDSCs或模拟非癌性（NC）-MDSCs。我们发现肿瘤性MDSCs差异表达一组激酶核心，这些激酶控制着谱系特异性（PI3K-AKT和SRC激酶）和癌症诱导（ERK和PKC激酶）的蛋白质相互作用网络（互作组）。这些激酶在一定程度上促进髓系分化。然而，只有AKT和ERK特异性驱动MDSC从髓系前体细胞分化。用选择性小分子抑制剂或短发夹RNA（shRNAs）干扰AKT和ERK可选择性地阻碍MDSC分化和生存能力。因此，我们提供了令人信服的证据，表明MDSCs构成了一个独特的髓系谱系，其特征为“激酶特征”和明确的互作组。我们的结果为开发针对这些促进肿瘤的免疫细胞的抗癌治疗方法定义了新的机会。
