Targeting RIG-I activation to signal tumor cell killing and anti-tumor immunity in breast cancer

靶向 RIG-I 激活以发出乳腺癌肿瘤细胞杀伤和抗肿瘤免疫信号

基本信息

批准号：
9760312
负责人：
David Elion
金额：
$ 1.73万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2019-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9760312
关键词：
4T1 Agonist American Antitumor Response Antiviral Agents Apoptosis Binding Breast Breast Cancer Cell Breast Cancer Patient CASP1 gene CASP8 gene CASP9 gene CD8-Positive T-Lymphocytes Cancer cell line Caspase Cell Death Cell membrane Cells Cleaved cell Collection Cytometry Data Detection Disease Disease Progression Enzyme-Linked Immunosorbent Assay Flow Cytometry Gene Chips Genes Genetic Goals Human IFNAR1 gene IKK alpha IRF3 gene Immune Immune checkpoint inhibitor Immune response Immune system Immunity Immunologics Immunosuppression Immunosuppressive Agents Inflammasome Inflammatory Interferon Receptor Interferons Interleukin-1 Interleukin-10 Interleukin-18 Investigation JAK1 gene Leukocytes Malignant Neoplasms Mammary Neoplasms Measures Mediating Metastatic to Molecular Molecular Analysis Mus Nuclear Nucleotides Oligonucleotides Pathway interactions Patients Pharmacology Phosphorylation Population Production RNA RNA Helicase RNA Interference Regulation Role STAT1 gene Signal Pathway Signal Transduction TNF gene TNFSF10 gene TYK2 Testing Therapeutic Therapeutic Uses Transforming Growth Factors Tretinoin Tumor Immunity Tumor-Infiltrating Lymphocytes Viral Virus Virus Receptors Woman Xenograft procedure anti-PD-L1 anti-tumor immune response apoptotic protease-activating factor 1 arm base breast cancer survival cancer cell cancer diagnosis cancer therapy cancer type cell killing checkpoint therapy chemotherapy combinatorial cytokine experimental study immunogenic immunogenicity immunoreaction immunosuppressed improved outcome in vivo inhibitor/antagonist intravital imaging knock-down malignant breast neoplasm mimetics molecular array neoplastic cell novel strategies novel therapeutic intervention promoter receptor recruit response therapeutic candidate transcription factor tumor tumor growth tumor immunology tumor microenvironment viral RNA

项目摘要

Abstract/ Project Summary Immune checkpoint inhibitors used to treat patients with cancer can enhance adaptive anti-tumor immunity and are remarkably efficacious, but produce durable responses on only 10-15% of patients, warranting additional studies of tumor immunity. Little is known about how cancers might respond to treatments that activate intrinsic immunity, the collection of molecular pathways present in nearly all cells that provide first-line recognition of, and protection against, viruses. Activation of endogenous viral oligonucleotide receptors, such as RIG-I, could be used therapeutically as a way to jumpstart an otherwise immunosuppressed tumor microenvironment (TME). Once RIG-I binds to viral RNA, RIG-I signaling potently induces activity of pro- inflammatory transcription factors IRF3 and NF-B, activating expression of pro-inflammatory cytokines. Simultaneously, RIG-I activates the caspase-1 dependent inflammasome, which initiates an immunogenic form of programmed cell death termed `pyroptosis.' In the cancer setting, pyroptosis in combination with pro- inflammatory cytokines could be therapeutically efficacious. Although RIG-I signaling has not been well-studied in breast cancers, a cancer type often considered immunologically `cold,' my preliminary data shows that breast cancer cells treated with a synthetic RIG-I mimetic undergo cell death, and produce an abundance of the pro-inflammatory cytokine interferon (IFN)- and TRAIL. Further, we have used the RIG-I mimetic to treat mouse mammary tumors in vivo, finding decreased tumor growth and increased tumor cell death, consistent with the hypothesis that activation of intrinsic immunity in breast cancers will induce pyroptosis, expression of pro-inflammatory cytokines, and increase tumor infiltrating lymphocytes. We propose three Aims to test this hypothesis. Aim 1 will focus on the molecular mechanism(s) by which RIG-I signaling induces cell death in breast cancer cells. Aim 2 will identify cytokines induced by RIG-I in breast cancer cells, and the molecular pathways regulating their expression downstream of RIG-I activation. Aim 3 will focus on how therapeutic RIG-I signaling impacts mammary tumor leukocyte populations in vivo, as well as how RIG-I signaling effects immune checkpoint inhibitor therapy in breast cancer. We will employ a combination of detailed molecular analyses, unbiased molecular arrays, mass cytometry (CyTOF), and intravital imaging to question how RIG-I activation might impact disease progression in breast cancers.

摘要/项目摘要用于治疗癌症特定性的免疫检查点抑制剂可以增强自适应抗肿瘤免疫力，具有显着有效性，但仅对10-15％的患者产生持久反应，保证肿瘤免疫的其他研究。激活内在免疫力的处理，几乎所有细胞中存在的分子途径的收集提供对病毒的一线识别和保护。可以在治疗上使用诸如RIG-I之类的受体作为一种启动原本免疫的方式肿瘤微环境（TME）。炎症转录因子IRF3和NF-B，激活促炎细胞因子的表达。同时，rig-i激活caspase-1依赖性炎症体，该炎症体引发了免疫原性形式在癌症环境中称为“凋亡”的程序性细胞死亡炎性细胞因子可能在治疗上是有效的。尽管RIG-I信号传导在乳腺癌中尚未得到充分研究，但癌症类型通常在免疫学上“冷”，我的初步数据表明，用合成RIG-I治疗的癌细胞模仿细胞死亡，并产生大量的促炎性细胞因子干扰素（IFN） - 和进一步。肿瘤生长并增加肿瘤细胞死亡，这与固有激活的假设一致乳腺癌的免疫力诱导凋亡，促炎细胞因子的表达，和增加肿瘤浸润的淋巴细胞。 RIG-I信号传导诱导乳腺癌细胞中的细胞死亡的分子机制。鉴定RIG-1在乳腺癌细胞中诱导的细胞因子，以及调节其调节的分子途径 RIG-I激活下游的表达将集中于治疗性RIG-I信号的影响体内乳腺白细胞种群乳腺癌的抑制剂疗法。分子阵列，质量细胞仪（cytof）和插入式成像，以质疑RIG-I激活如何激活影响乳腺癌的疾病进展。