Restoring the Regulation of a Central Signaling Pathway to Prevent Metastases and Reinstate Tumor Immunity

恢复中央信号通路的调节以预防转移并恢复肿瘤免疫

• 批准号: 9891885
• 负责人: Eduardo V Davila
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891885
• 关键词: ADORA2A gene; Accounting; Adenosine; Age; Cancer Etiology; Cell Line; Cell Mobility; Cells; Cellular Morphology; Cessation of life; Chronic; Clinical; Cytoskeleton; Data; Development; Disseminated Malignant Neoplasm; Distal; Endothelial Cells; Engineering; Exhibits; FDA approved; FMR1; Family; Family member; Functional disorder; Gene Chips; Generations; Genes; Genetic; Genetic Transcription; Goals; Homeobox; Human; IRAK1 gene; ITGA11 gene; Immunity; Immunotherapy; Impairment; In Vitro; Inflammatory; Integrins; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Interruption; Invaded; Lead; Link; Malignant Neoplasms; Mediating; Medical; Melanoma Cell; Metastatic Melanoma; Metastatic to; Modeling; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Myeloid-derived suppressor cells; Names; Neoplasm Metastasis; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Platelet-Derived Growth Factor; Play; Population; Pre-Clinical Model; Process; Production; Property; Proteins; Recurrence; Regulation; Reporting; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Survival Rate; T cell response; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Toll-like receptors; Tumor Immunity; Vascular Endothelial Growth Factors; Veterans; anti-tumor immune response; base; cancer cell; cancer immunotherapy; cancer therapy; cancer type; cell motility; clinically relevant; effective therapy; exhaustion; experience; extracellular; genetic approach; high risk; in vivo; insight; interleukin-1 receptor-associated kinase; knock-down; melanoma; member; metastatic process; mortality; neoplastic cell; novel; novel strategies; overexpression; prevent; receptor; standard of care; success; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression

Our long-term goals are to understand the mechanisms by which IL-1 receptor associated kinase-M (IRAK- M) expression in melanoma regulates metastasis and to develop clinically-relevant approaches to induce and sustain anti-tumor T cell immunity by restoring IRAK-M expression. Cancer metastasis is the main cause of cancer mortality and morbidity, accounting for 90% of cancer-related deaths. Immunotherapy has revolutionized the treatment of advanced (metastatic) melanoma and is now the standard of care for most patients. Despite these successes however, clinical benefits are restricted to small percentage of patients. An underlying and universal hindrance to immunotherapies is a variety of immunosuppressive mechanisms that in large part originate from the chronic expression of inflammatory signals. Understanding the fundamental mechanisms that regulate these factors and targeting these pathways is critical for developing effective strategies to prevent or reduce metastases and to restore antitumor T cell activity. We previously reported that the IL-1 receptor associated kinase-4 (IRAK-4) is overexpressed and activated in melanoma. IRAK-4 is a central kinase in the inflammatory process that also regulates the expression of metastases-promoting and immunosuppressive molecules (including ATP, VEGF PDGF, IL-1). This signaling pathway is activated by IL- 1 receptor and toll-like receptors. We previously reported that inhibiting IRAK-4 activity in melanoma drastically reduces the expression of many of these inflammatory factors and reduces cancer progression in mice. By examining the levels of endogenous proteins that normally inhibit IRAK-4 signaling we found IRAK-M to be deficient in melanomas (patients and cell lines). IRAK-M is unique among the IRAK family members in that it is a negative regulator of inflammatory IRAK-4 signaling. We found that restoring IRAK-M expression in melanoma cells drastically reduced their ability to invade (in vitro) and to metastasize (in preclinical models). This was associated with changes in the expression levels of key molecules associated with cell mobility, cytoskeletal dynamics, and formation of lamellipodium in non-cancerous cells but their role in melanoma or metastasis is unknown. These molecules include Distal-Less Homeobox 5 (DLX5; a factor with transcription activating and repressing activity), the integrin ITGA11, and cytoplasmic FMR1 Interacting Protein 2 (Cyfip2). Furthermore, we observed that IRAK-4 signaling in melanoma accelerated T cell dysfunction while inhibiting IRAK-4 enhanced antitumor T cell activity. IRAK-4’s ability to alter T cell activity was associated with its ability to regulate extracellular ATP levels; ATP’s metabolite, adenosine, strongly suppresses T cell activity. Through these studies, we will test the hypothesis that restoring IRAK-M expression in melanoma impairs their metastatic potential by regulating the expression of DLX5 which in turn regulates cell invasion. We further postulate that IRAK-M expression in cancer cells restores antitumor T cell activity by reducing the expression levels of and signals originating from extracellular ATP. In Aim 1, we will determine the mechanism by which IRAK-M regulates cancer cell invasion. This aim builds on compelling preliminary data indicating that IRAK-M induction in cancer cells impairs their ability to invade through matrix or endothelial cells (in vitro) and to metastasize (in vivo). We conjecture that DLX5 upregulates ITGA11 but downregulates Cyfip2 expression thereby controlling cell migration, cell morphogenesis and invasion. Through Aim 2, we propose to restore tumor immunity by reinstating IRAK-M signaling in tumor cells. We will use genetic approaches and a predefined panel of drugs, that selectively induce IRAK-M in melanoma, to investigate the cellular and molecular mechanisms by which IRAK-M enhances anti-tumor T cell activity. These studies have the potential to provide mechanistic insights as to how IRAK-M regulate cancer cell metastasis and opportunities to develop clinically relevant, novel strategies to restore tumor immunity.

我们的长期目标是了解 IL-1 受体相关激酶 M (IRAK- M) 黑色素瘤中的表达调节转移并开发临床相关方法来诱导和 通过恢复IRAK-M表达来维持抗肿瘤T细胞免疫是癌症转移的主要原因。 癌症死亡率和发病率，占癌症相关死亡的 90%。 彻底改变了晚期（转移性）黑色素瘤的治疗方法，现已成为大多数患者的护理标准 然而，尽管取得了这些成功，但临床获益仅限于一小部分患者。 免疫治疗的潜在和普遍障碍是多种免疫抑制机制， 很大程度上源于对炎症信号慢性表达的根本认识。 调节这些因素并针对这些途径的机制对于提高有效性至关重要 我们之前报道过预防或减少转移以及恢复抗肿瘤 T 细胞活性的策略。 IL-1 受体相关激酶 4 (IRAK-4) 在黑色素瘤中过度表达并被激活。 炎症过程中的中心激酶，还调节促进转移和 免疫抑制分子（包括 ATP、VEGF PDGF、IL-1）。该信号通路由 IL- 激活。 我们之前报道过抑制黑色素瘤中的IRAK-4活性。 显着降低许多炎症因子的表达并减少癌症进展 通过检查通常抑制 IRAK-4 信号传导的内源性蛋白质的水平，我们发现了 IRAK-M。 黑色素瘤（患者和细胞系）缺乏 IRAK-M 在 IRAK 家族成员中是独一无二的。 我们发现它是炎症 IRAK-4 信号传导的负调节因子，可恢复 IRAK-M 的表达。 黑色素瘤细胞的侵袭（体外）和转移（临床前模型）能力显着降低。 这与细胞迁移性相关关键分子表达水平的变化有关， 细胞骨架动力学，以及非癌细胞中片状伪足的形成，但它们在黑色素瘤或 这些分子包括远端同源盒 5（DLX5；一种转录因子）。 激活和抑制活性）、整合素 ITGA11 和细胞质 FMR1 相互作用蛋白 2 (Cyfip2)。 此外，我们观察到黑色素瘤中的 IRAK-4 信号传导加速了 T 细胞功能障碍，同时抑制了 IRAK-4 增强抗肿瘤 T 细胞活性 IRAK-4 改变 T 细胞活性的能力与其能力相关。 调节细胞外 ATP 水平；ATP 的代谢物腺苷强烈抑制 T 细胞活性。 在这些研究中，我们将检验以下假设：恢复黑色素瘤中的 IRAK-M 表达会损害其 我们通过调节 DLX5 的表达来调节细胞的侵袭能力。 进一步假设癌细胞中的 IRAK-M 表达通过降低 T 细胞的抗肿瘤活性来恢复抗肿瘤 T 细胞活性。 在目标 1 中，我们将确定细胞外 ATP 的表达水平和信号。 IRAK-M 调节癌细胞侵袭的机制这一目标建立在令人信服的初步数据的基础上。 表明癌细胞中的 IRAK-M 诱导削弱了它们通过基质或内皮细胞侵袭的能力 我们推测DLX5上调ITGA11但下调ITGA11。 Cyfip2 表达从而控制细胞迁移、细胞形态发生和侵袭。通过目标 2，我们。 建议通过恢复肿瘤细胞中的 IRAK-M 信号来恢复肿瘤免疫力，我们将使用遗传手段。 方法和一组预定义的药物，选择性诱导黑色素瘤中的 IRAK-M，以研究 这些研究揭示了 IRAK-M 增强抗肿瘤 T 细胞活性的细胞和分子机制。 有可能提供关于 IRAK-M 如何调节癌细胞转移的机制见解 有机会开发临床相关的新策略来恢复肿瘤免疫。