Role of myeloid-derived suppressor cells in local and systemic immunosuppression in glioblastoma

髓源性抑制细胞在胶质母细胞瘤局部和全身免疫抑制中的作用

基本信息

批准号：
10837997
负责人：
Defne Bayik Watson
金额：
$ 8.04万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-07 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10837997
关键词：
ATAC-seq Address Animal Model Automobile Driving Behavior Biological Cells Circulation Clinical Trials Complement Development Disease Outcome Epigenetic Process Female Foundations Glioblastoma Histones Immunosuppression Immunotherapy Incidence Individual Infiltration Interleukin-1 beta Intervention Intrinsic factor Lead Lysine Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Myeloid-derived suppressor cells OX40 Pathway interactions Patient-Focused Outcomes Patients Peripheral Play Pre-Clinical Model Predisposition Primary Brain Neoplasms Prognosis Regulation Role Specimen T-Cell Activation Testing Tumor Immunity Variant anti-CTLA4 anti-PD-1 anti-tumor immune response biological sex complement pathway complement system drug repurposing efficacy evaluation epigenetic regulation epigenetic variation fludarabine genetic signature granulocyte improved in vitro activity in vivo inhibitor insight male monocyte novel pharmacologic response sex success therapy resistant treatment response tumor tumor progression tumor-immune system interactions tumorigenesis

项目摘要

PROJECT SUMMARY: Glioblastoma (GBM) is the most common primary malignant brain tumor, with a median survival of up to 20 months. Males have a 1.6-fold higher incidence of GBM compared to females and worse disease outcomes. Immunotherapies, which are currently in clinical trials, have had limited success in improving patient outcomes. An immunosuppressive microenvironment facilitating tumor progression and restricting anti- tumor immune response likely underlies therapeutic resistance. Although the accumulation of myeloid-derived suppressor cells (MDSCs) plays a critical role in the establishment of this immunosuppressive milieu, the mechanisms by which individual MDSC subsets promote tumorigenesis and are regulated remain poorly defined. We previously demonstrated that monocytic MDSCs (mMDSCs) infiltrated male tumors at higher rates in preclinical models and patient specimens. In contrast, granulocytic MDSCs (gMDSCs) expand in the peripheral circulation of female animal models and the gMDSC gene signature is associated with poor prognosis in female patients. This variation in MDSC subsets also informed sex-specific therapeutic responses to fludarabine and anti-IL-1β in preclinical models. More recently, we observed that mMDSCs and gMDSCs have a distinct epigenetic landscape, which is also informed by biological sex. While this highlights the potential role of epigenetic regulation of MDSC subset activity, there is limited insight into the mechanisms driving distinct MDSC subset functions. Our preliminary results suggested that the complement pathway could be one such mechanism as complement component 1q (C1q) was highly expressed by gMDSCs and elevated in females. Based on these observations, we hypothesize that epigenetic regulation of C1q informs sex-specific behavior of MDSC subsets and epigenetic reprogramming of MDSCs will improve the efficacy of T cell-activating strategies. Specific Aim 1 will test the hypothesis that the unique epigenetic signatures of MDSC subsets make them susceptible to different histone modifiers that can be combined with checkpoint modulators. Sub-Aim 1A will examine the efficacy of histone lysine demethylase inhibitors on MDSC activity in vitro and in vivo, while Sub-Aim 1B will attempt to achieve durable anti-tumor immune response by combining lead inhibitors with anti-PD-1, anti-CTLA- 4, and anti-OX40. Specific Aim 2 will test the hypothesis that the C1q locus is differentially accessible between male versus female MDSC subsets. Sub-Aim 2A will use ATAC-seq and CUT & RUN to evaluate the epigenetic landscape of complement proteins and specific histone mark occupancy based on the differential histone lysine demethylase expression profile. Sub Aim 2B will use pharmacological inhibitors to test the sex-specific effect of histone lysine demethylases on complement regulation. These studies lay the foundation for the development of epigenetic modifiers for GBM immunotherapies by addressing variations in anti-tumor immunity, repurposing drugs, and defining targetable pathways. These results are broadly applicable to other cancers and can lead to advanced treatment opportunities and improved patient outcomes.

项目摘要：胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤，中位数最多20个月的生存。与女性相比，男性的GBM事件高1.6倍，而且更糟疾病结果。当前正在临床试验中的免疫疗法在改善方面取得了有限的成功患者的结果。免疫抑制性微环境促进肿瘤进展并限制抗肿瘤免疫反应可能是治疗性抗性的基础。虽然髓样衍生的积累抑制细胞（MDSC）在建立这种免疫抑制环境中起着至关重要的作用单个MDSC亚群促进肿瘤发生并受到调节的机制仍然很差。我们先前证明了单核细胞MDSC（MMDSC）以较高的速率浸润的雄性肿瘤临床前模型和患者标本。相反，粒细胞MDSC（GMDSC）在周围扩展女性动物模型和GMDSC基因签名的循环与女性预后不良有关患者。 MDSC子集的这种差异还告知对氟达拉滨和临床前模型中的抗IL-1β。最近，我们观察到MMDSC和GMDSC具有独特的表观遗传景观，也以生物学的方式告知。虽然这突出了 MDSC子集活性的表观遗传调节，对驱动不同MDSC的机制的洞察力有限子集功能。我们的初步结果表明，完成途径可能是这样的机制由于完成成分1Q（C1Q）由GMDSC高度表达，并在女性中升高。基于这些观察结果，我们假设C1Q的表观遗传调节为MDSC子集的性别特定行为提供了信息 MDSC的表观遗传重编程将提高T细胞激活策略的效率。具体目标 1将检验以下假设：MDSC子集的独特表观遗传学特征使它们容易受到影响可以与检查点调节器结合使用的不同的Hisstone修饰符。 Sub-aim 1a将检查组蛋白赖氨酸脱甲基酶抑制剂在体外和体内对MDSC活性的功效，而Sub-aim 1b将试图通过将铅抑制剂与抗PD-1，抗CTLA-结合在一起来实现持久的抗肿瘤免疫响应 4和抗OX40。具体目标2将检验以下假设：男性与女性MDSC子集。 Sub-aim 2a将使用ATAC-SEQ并剪切和运行来评估表观遗传基于差异组蛋白的歌词去甲基酶表达谱。 SUB AIM 2B将使用药物抑制剂来测试特定的性别效应组蛋白赖氨酸脱甲基酶完成调节。这些研究为发展奠定了基础 GBM免疫疗法的表观遗传修饰剂通过解决抗肿瘤免疫史的变化，重新利用药物和定义可靶向途径。这些结果广泛适用于其他癌症，可以导致高级治疗机会并改善了患者的预后。