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

基本信息

批准号：
10464895
负责人：
Alexander Emmanuelli
金额：
$ 4.68万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
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/10464895
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

项目摘要

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.

项目摘要/摘要：卵巢癌（OVCA）是美国最威胁生命的妇科恶性肿瘤每年夺去14,000名妇女的生命。转移性OVCA的5年生存率为27％，并且标准疗法和疗法，例如化学疗法和手术干预，在很大程度上是无效的，并且通常可以促进癌症的耐药性和复发性。癌症免疫疗法的最近冒险事实证明，在治疗其他癌症方面有效，但在OVCA中的效率最低。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是曲折的。卵巢肿瘤已经发展了策略，使它们能够在不利条件下繁衍生息，同时抑制免疫细胞的受保护功能。最近的研究表明，这些癌症激起了严重的髓样细胞中的代谢应激以逃避免疫控制，但髓样细胞如何尚不清楚肿瘤环境中的综合和解释的代谢应激信号。我们的小组确定了这种不利的肿瘤微环境中的条件破坏了内质网的蛋白质折叠能力（ER）在浸润免疫细胞中。这个过程会导致“ ER应力”，并通过IRE1α-XBP1引起持续的响应途径，改变抗肿瘤的主动和维持所需的关键免疫代谢过程免疫。多项研究表明，髓样衍生的抑制细胞（MDSC）和中性粒细胞可以通过从TME中耗尽关键氨基酸来调节抗肿瘤T细胞的功能。我们的初步发现表明需要IRE1α-XBP1信号传导来维持MDSC表达精氨酸酶1（ARG1）和通过未知机制抑制T细胞增殖。该提案的主要目标是识别和了解与肿瘤相关的髓样细胞中ER应激的转录和功能后果。因此，我们的中心假设是，ER应力传感器的适应不良激活调节通过改变其转录编程以诱导免疫抑制作用，髓样细胞子集在肿瘤中表型。特别是，我们假设IRE1α激活的XBP1转录因子是直接 ARG1的转录诱导剂。我们还假设ER应力驱动的基因特征将描述新的由IRE1α-XBP1控制的转录程序在肿瘤相关的中性粒细胞中。最后，我们将定义如何肿瘤相关的中性粒细胞中的IRE1α-XBP1消融调节T细胞和T细胞的细胞毒性活性受保护的抗肿瘤免疫的发展。了解肿瘤中质网应激的后果相关的髓样细胞对于全面定义卵巢癌的T细胞功能障碍至关重要，而对开发新的治疗干预措施，以增加HARMSH肿瘤微环境中T细胞效应的能力。拟议的项目在机械上和翻译上具有相关性，因为它有可能发现应力信号控制肿瘤中髓样细胞的调节表型。