Immunosuppressive Programs Driven by IRE1 signaling in ovarian cancer

卵巢癌中 IRE1 信号驱动的免疫抑制程序

• 批准号: 10313801
• 负责人: Alexander Emmanuelli
• 金额: $ 4.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10313801
• 关键词: Ablation; Amino Acids; Arginine; Binding Sites; Biological Assay; Cancer Control; Cell physiology; Cells; Complex; Data; Development; Drug resistance; Endoplasmic Reticulum; Flow Cytometry; Functional disorder; Genetic Transcription; Genotype; Goals; Granzyme; Human; ITGAM gene; Immune; Immune Evasion; Immunotherapy; Infiltration; Interferon Type II; Interleukin-13; Interleukin-4; Knockout Mice; Knowledge; Life; Maintenance; Malignant - descriptor; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Metabolic stress; Metastatic Malignant Neoplasm to the Ovary; Molecular; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Operative Surgical Procedures; Ovarian Carcinoma; Pathway interactions; Pharmacology; Phenotype; Pre-Clinical Model; Process; Publishing; Refractory; Role; STAT6 gene; Signal Transduction; Stress; Survival Rate; T cell response; T-Cell Activation; T-Cell Development; T-Cell Proliferation; T-Lymphocyte; Transactivation; Transgenic Mice; Translations; Tumor Immunity; Tumor-infiltrating immune cells; United States; Woman; XBP1 gene; adaptive immunity; anti-cancer; arginase; base; cancer immunotherapy; cancer recurrence; chemotherapy; conditional knockout; cytokine; cytotoxic; effective therapy; effector T cell; endoplasmic reticulum stress; genetic signature; granulocyte; immune function; immunoregulation; improved; misfolded protein; neutrophil; novel strategies; novel therapeutic intervention; ovarian neoplasm; personalized immunotherapy; programs; promoter; protein folding; response; sensor; standard care; success; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumor progression

PROJECT SUMMARY/ABSTRACT: Ovarian Carcinomas (OvCa) are the most life-threatening gynecological malignancy in the United States, claiming the lives of 14,000 women every year. The 5-year survival rate for metastatic OvCa is 27%, and standard treatments and therapies such as chemotherapy and surgical intervention are largely ineffectual, and can often promote drug resistance and recurrence of the cancer. The recent advent of cancer immunotherapy has proven effective in treating other cancers, but shown minimal efficacy in OvCa. Understanding the mechanisms that enable OvCa to escape immune control is crtical to developing more effective treatments. Ovarian Tumors have evolved strategies that enable them to thrive under adverse conditions while suppressing the protective function of immune cells. Recent studies demonstrate that these cancers provoke severe metabolic stress in myeloid cells to escape immune control, but it remains unknown how myeloid cells integrate and interpret metabolic stress signals in the tumor milieu. Our group determined that adverse conditions in the tumor microenvironment disrupt the protein-folding capacity of the endoplasmic reticulum (ER) in infiltrating immune cells. This process causes “ER stress” and elicits persistent responses via the IRE1α-XBP1 pathway, that alter key immunometabolic processes required for the initiation and maintenance of anti-tumor immunity. Multiple studies have shown that myeloid derived suppressor cells (MDSCs) and neutrophils can regulate anti-tumor T cell functions by depleting key amino acids from the TME. Our preliminary findings indicate that IRE1α-XBP1 signaling is required to sustain the capacity of MDSCs to express Arginase 1 (Arg1) and suppress T cell proliferation, by an unknown mechanism. The main goal of this proposal is to identify and understand the transcriptional and functional consequences of ER stress in tumor associated myeloid cells. Therefore, our central hypothesis is that maladaptive activation of ER stress sensors regulates the function of myeloid cell subsets in the tumor by altering their transcriptional programming to induce immunosuppressive phenotypes. Specifically, we postulate that the IRE1α-activated XBP1 transcription factor is a direct transcriptional inducer of Arg1. We also hypothesize that ER stress-driven gene signatures will delineate new transcriptional programs controlled by IRE1α-XBP1 in tumor associated neutrophils. Lastly, we will define how IRE1α-XBP1 ablation in tumor associated neutrophils modulates the cytotoxic activity of T cells and the development of protective anti-tumor immunity. Understanding the consequences of ER stress in tumor associated myeloid cells will be crucial to comprehensively define T cell dysfunction in ovarian cancer, and to develop new therapeutic interventions that augment T cell effector capacity in a harsh tumor microenvironment. The proposed project is mechanistically and translationally relevant as it has the potential to uncover how stress signals govern the regulatory phenotypes of myeloid cells in the tumor.

项目总结/摘要： 卵巢癌（OvCa）是美国最危及生命的妇科恶性肿瘤， 每年夺走14,000名女性的生命转移性OvCa的5年生存率为27%， 标准的治疗和疗法如化疗和手术干预在很大程度上是无效的， 往往会促进癌症的耐药性和复发。癌症免疫疗法的最新进展 已经证明在治疗其他癌症中有效，但在OvCa中显示出最小的功效。了解 使OvCa能够逃脱免疫控制的机制对于开发更有效的治疗方法至关重要。 卵巢肿瘤已经进化出了使它们能够在不利条件下茁壮成长的策略， 免疫细胞的保护功能。最近的研究表明，这些癌症引起严重的 代谢应激的骨髓细胞逃避免疫控制，但它仍然是未知的骨髓细胞如何 整合并解释肿瘤环境中的代谢应激信号。我们的团队确定， 肿瘤微环境中的条件破坏内质网（ER）的蛋白质折叠能力 免疫细胞的浸润这一过程导致“ER应激”，并通过IRE 1 α-XBP 1引起持续性反应。 途径，其改变启动和维持抗肿瘤免疫应答所需的关键免疫代谢过程。 免疫力多项研究表明，髓源性抑制细胞（MDSC）和嗜中性粒细胞可以 通过消耗TME中的关键氨基酸来调节抗肿瘤T细胞功能。我们的初步调查结果显示 IRE 1 α-XBP 1信号传导是维持MDSC表达精氨酸酶1（Arg 1）的能力所必需的， 通过未知机制抑制T细胞增殖。该提案的主要目标是确定和 了解肿瘤相关髓系细胞中ER应激的转录和功能后果。 因此，我们的中心假设是，内质网应激感受器的适应不良激活调节了细胞的功能。 通过改变其转录编程以诱导免疫抑制， 表型具体来说，我们假设IRE 1 α激活的XBP 1转录因子是直接的转录因子。 Arg 1的转录诱导因子。我们还假设内质网应激驱动的基因特征将描绘新的 肿瘤相关中性粒细胞中由IRE 1 α-XBP 1控制的转录程序。最后，我们将定义如何 肿瘤相关中性粒细胞中的IRE 1 α-XBP 1消融调节T细胞的细胞毒活性， 保护性抗肿瘤免疫的发展。了解ER应激在肿瘤中的后果 相关的骨髓细胞对于全面定义卵巢癌中的T细胞功能障碍至关重要， 开发新的治疗干预措施，增强T细胞在恶劣的肿瘤微环境中的效应能力。 拟议的项目是机械和预防相关的，因为它有可能揭示如何 应激信号控制肿瘤中骨髓细胞的调节表型。