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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：
10746880
负责人：
Defne Bayik Watson
金额：
$ 24.9万
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/10746880
关键词：
Accounting Address Adoptive Transfer Attenuated Behavior Biological Blood Vessels Bone Marrow CAR T cell therapy Cancer Vaccines Cell Lineage Cell Proliferation Cells Chimera organism Circulation Clinical Trials Complement Development Disease Disease Outcome Female Foundations Frequencies Gene Expression Profile Generations Germ Cells Glioblastoma Growth Immune Evasion Immune checkpoint inhibitor Immune response Immunity Immunosuppression Immunotherapeutic agent Immunotherapy Impairment In Vitro Incidence Individual Infiltration Interleukin-1 beta Intervention Knock-out Laboratories Left Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mediating Mediator Mus Myeloid-derived suppressor cells OX40 Oncolytic viruses Pathogenesis Pathway Analysis Pathway interactions Patient-Focused Outcomes Patients Peripheral Pharmaceutical Preparations Phase Play Population Heterogeneity Pre-Clinical Model Predisposition Primary Brain Neoplasms Production Prognosis Regulation Reporting Research Role Serum Sex Differences T-Cell Activation T-Lymphocyte and Natural Killer Cell Testing Therapeutic Tumor Immunity Tumor-associated macrophages Variant antagonist anti-CTLA4 anti-PD-1 anti-tumor immune response autocrine cancer stem cell chemotherapy clinical efficacy clinically relevant complement system density drug candidate drug repurposing efficacy evaluation experimental study fludarabine genetic signature granulocyte immune activation immune checkpoint improved in vitro activity in vivo inhibitor insight male monocyte neoplastic cell novel pharmacologic polarized cell programs receptor response sex standard of care stem cell self renewal success therapeutic target therapy outcome therapy resistant transcriptome treatment response tumor tumor growth tumor microenvironment 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 outcome. Standard-of-care treatment and immunotherapies, which are currently in clinical trials, have had limited success improving patient outcome. An immunosuppressive microenvironment facilitating tumor progression and restricting anti-tumor immune response likely underlies therapeutic resistance. Although myeloid-derived suppressor cell (MDSCs) accumulate in patients with malignancies and play a critical role in the establishment of this immunosuppressive milieu, the mechanisms by which individual MDSC subsets promote tumorigenesis remain poorly defined. In pre-clinical models, I demonstrated that monocytic MDSCs (mMDSCs) infiltrated tumor at higher rates in males, while granulocytic MDSCs (gMDSCs) were more abundant in the peripheral circulation of females. Furthermore, there were more immunosuppressive myeloid cells in the tumors of male patients and gMDSC gene signature associated with poor prognosis of female patients. MDSC subset variation also determined sex-specific therapeutic response in preclinical models, including to fludarabine and anti-IL-1β. I also established that complement component 1q (C1q) is highly expressed by gMDSCs and elevated in females. Based on these observations, I hypothesize that MDSC subsets promote GBM progression via distinct mechanisms in a sex-specific manner and that their targeting will improve the efficacy of T cell-activating strategies. Specific Aim 1 will test the hypothesis that mMDSCs and gMDSCs have distinct roles in local and systemic immunosuppression in a sex-specific manner. This aim will investigate the changes in tumor growth, vascular density and immune activation status by adoptively transferring MDSC subsets and selectively depleting MDSCs in bone marrow chimeras. Specific Aim 2 will test the hypothesis that the unique gene expression signatures of MDSC subsets makes them susceptible to distinct drugs that can be combined with checkpoint modulators. Sub-Aim 2A will examine the efficacy of drug candidates on MDSC activity in vitro and in vivo, while Sub-Aim 2B will attempt to achieve durable anti-tumor immune response by combining MDSC targeting strategies with anti-PD-1, anti-CTLA-4 and anti-OX40. Specific Aim 3 will test the hypothesis that gMDSC- derived C1q promotes MDSC lineage commitment and systemic immunosuppression by evaluating tumor progression and checkpoint response in the absence of C1q. Sub-Aim 3A will use C1qa knockout bone marrow and C1q receptor inhibitors to determine MDSC fate. Sub Aim 3B will use pharmacological inhibitors combined with checkpoint modulators. These studies lay the foundation for my future research program and the development of novel immunotherapies for GBM 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 outcome.

项目摘要：胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤，发病率中位