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: 10618915
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618915
• 关键词: ADORA2A gene; Acceleration; Accounting; Adenosine; Age; Cancer Etiology; Cell Line; Cell Mobility; Cells; Cellular Morphology; Cessation of life; Chronic; Clinical; Cytoplasm; 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; Link; Malignant Neoplasms; Mediating; Medical; Melanoma Cell; Metastatic Melanoma; Metastatic to; Metastatic/Recurrent; 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; Repression; 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; 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; novel therapeutic intervention; overexpression; prevent; receptor; standard of care; success; 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-）的机制