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：
10323691
负责人：
Defne Bayik Watson
金额：
$ 12.05万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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：
2021-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323691
关键词：
Accounting Address Adoptive Transfer Attenuated Behavior Biological Blood Circulation Blood Vessels Bone Marrow CAR T cell therapy Cancer Vaccines Cell Lineage Cell Proliferation Cells Chimera organism 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 Interleukin-1 beta Intervention Knock-out Laboratories Lead Left Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mediating Mediator of activation protein Mus Myeloid-derived suppressor cells OX40 Oncolytic viruses Pathogenesis Pathway Analysis Pathway interactions Patient-Focused Outcomes Patients Peripheral Pharmaceutical Preparations Pharmacology Phase Play Population Heterogeneity Pre-Clinical Model Primary Brain Neoplasms Production Prognosis Program Development Regulation Reporting Research Role Serum Sex Differences T-Lymphocyte 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 base 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 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，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。目前正在临床试验中的护理标准治疗和免疫疗法已有成功改善了患者的结果。支持肿瘤的免疫抑制微环境抗肿瘤免疫反应的进展和限制可能是治疗性抗性的基础。虽然髓样衍生的抑制细胞（MDSC）在恶性肿瘤患者中积累，并在建立这种免疫抑制环境，即单个MDSC子集促进的机制肿瘤发生的定义仍然很差。在临床前模型中，我证明了单核细胞MDSC（MMDSC）男性浸润肿瘤的浸润较高，而粒细胞MDSC（GMDSC）在该肿瘤中更为丰富女性的外围循环。此外，肿瘤中有更多的免疫抑制髓样细胞男性患者和GMDSC基因签名与女性患者预后不良有关。 MDSC子集变异还确定了临床前模型中的性别特异性治疗反应，包括氟达拉滨和抗IL-1β。我还确定完成组件1Q（C1Q）由GMDSC高度表达并升高在女性中。基于这些观察结果，我假设MDSC子集通过以性别特定方式的不同机制，其靶向将提高T细胞激活的效率策略。具体目标1将检验以下假设：MMDSC和GMDSC在局部和以性别特定方式进行全身免疫抑制。这个目标将调查肿瘤生长的变化，通过自适应转移MDSC子集和选择性耗尽，血管密度和免疫激活状态骨髓嵌合体中的MDSC。特定目标2将检验独特基因表达的假设 MDSC子集的签名使它们容易受到可与检查点结合的不同药物的影响调节器。 Sub-aim 2a将检查候选药物在体外和体内对MDSC活性的效率，而 Sub-aim 2b将尝试通过组合MDSC靶向来实现持久的抗肿瘤免疫响应抗PD-1，抗CTLA-4和抗OX40的策略。特定目标3将检验GMDSC-的假设得出的C1Q通过评估肿瘤来促进MDSC谱系承诺和全身免疫抑制在没有C1Q的情况下，进程和检查点响应。 Sub-aim 3A将使用C1QA敲除骨髓和C1Q受体抑制剂以确定MDSC命运。 Sub Aim 3B将使用合并的药物抑制剂带有检查点调节器。这些研究为我的未来研究计划和通过解决抗肿瘤免疫史的差异，重新利用的新型免疫疗法开发GBM的新型免疫疗法药物和定义目标途径。这些结果广泛适用于其他癌症，可以导致先进的治疗机会和改善患者结果。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Preinvasive to Invasive: PD-1-Expressing Macrophages Shift Lung Cancer into High Gear.

侵袭前到侵袭：表达 PD-1 的巨噬细胞使肺癌进入高速运转状态。

DOI：
10.1158/0008-5472.can-22-1802
发表时间：
2022
期刊：
Cancer research
影响因子：
11.2
作者：
Lee,Juyeun;Bayik,Defne;Lathia,JustinD
通讯作者：
Lathia,JustinD

SerpinB3 drives cancer stem cell survival in glioblastoma.

DOI：
10.1016/j.celrep.2022.111348
发表时间：
2022-09-13
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Lauko, Adam;Volovetz, Josephine;Turaga, Soumya M.;Bayik, Defne;Silver, Daniel J.;Mitchell, Kelly;Mulkearns-Hubert, Erin E.;Watson, Dionysios C.;Desai, Kiran;Midha, Manav;Hao, Jing;McCortney, Kathleen;Steffens, Alicia;Naik, Ulhas;Ahluwalia, Manmeet S.;Bao, Shideng;Horbinski, Craig;Yu, Jennifer S.;Lathia, Justin D.
通讯作者：
Lathia, Justin D.

All Glioblastoma Are Not Equal: Distinct Spatial Immune Profiles Between De Novo and Recurrent Tumors.

所有胶质母细胞瘤都不相同：新发肿瘤和复发肿瘤之间不同的空间免疫特征。