Impact of Circulating Myeloid Cell Clusters on Anti-Tumor Immunity
循环骨髓细胞簇对抗肿瘤免疫的影响
基本信息
- 批准号:10322156
- 负责人:
- 金额:$ 69.42万
- 依托单位:
- 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:2021-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:Active SitesAddressAdhesivesAdoptive Cell TransfersAdoptive TransferAdvanced Malignant NeoplasmAgonistAntibodiesAntigensAntineoplastic AgentsApoptosisBiological MarkersBloodBlood flowBreast Cancer ModelBreast MelanomaCD3 AntigensCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCancer PatientCell CommunicationCellsCellular immunotherapyClinicalClinical TrialsCluster AnalysisCoculture TechniquesComplexCytotoxic T-LymphocytesDataDestinationsDisseminated Malignant NeoplasmEffector CellEquilibriumExclusionFoundationsGeneticHomeHomingHumanICAM2 geneImmuneImmune checkpoint inhibitorImmunityImmunosuppressionImmunotherapeutic agentImmunotherapyIntegrinsIntercellular adhesion molecule 1L-SelectinLaboratoriesLeadLeukocytesLigandsLiver X ReceptorLymphocyteLymphocyte Homing ReceptorsMalignant NeoplasmsMammary NeoplasmsMediatingMemoryMetastatic breast cancerModelingMusMyeloid Cell SuppressionMyeloid CellsMyeloid-derived suppressor cellsNatural ImmunityNatural Killer CellsOutcomePatient SelectionPatientsPopulationPre-Clinical ModelPublishingRegimenResearchResidual stateResistanceSiteSolidSolid NeoplasmSpleenSplenectomyStructureSuppressor-Effector T-LymphocytesSystemT cell responseT cell therapyT memory cellT-LymphocyteTestingTherapeuticTissuesTravelTreatment EfficacyTumor ImmunityWorkadaptive immunityanti-cancerbaseblood-based biomarkercancer immunotherapycancer therapycheckpoint inhibitionchemokineclinically relevantcytotoxic CD8 T cellsdefined contributionfitnessgenetic approachimprovedin vivoinsightinterestlymph nodeslymphoid organmelanomamicroscopic imagingmouse modelnew therapeutic targetnovelpatient responsepreconditioningpredicting responsepredictive signaturepreventprognostic indicatorprognosticationprogramsreceptorrecruitresistance mechanismresponsestem cellstherapy resistanttraffickingtumortumor microenvironment
项目摘要
Durable outcomes in subsets of solid cancer patients treated with immune checkpoint inhibitors (ICI) or adoptive
cell transfer (ACT) immunotherapy has driven interest in gaining a better understanding of resistance
mechanisms that could identify novel druggable targets. Myeloid-derived suppressor cells (MDSC) have
emerged as one such barrier based on their ability to inhibit innate and adaptive immunity. While elevated blood
MDSC are recognized as a poor prognostic indicator in cancer patients, it is widely thought that the main effector
site for MDSC is within the tumor microenvironment (TME). This is in line with the well-documented contact-
dependent mechanisms involving short-lived intermediates that underlie known mechanisms of T cell
suppression by MDSC. Our published and preliminary studies enlarge on this view, showing that MDSC also
function outside the TME through an unprecedented mechanism of intravascular immune suppression. The
proposed study builds on our discovery that circulating MDSC initiate contact-dependent cleavage of the L-
selectin homing receptor on target T cells that substantially reduces antigen-driven expansion of cytotoxic T cells
in lymph nodes. We further found that L-selectin loss coincides with the formation of stable MDSC clusters in the
blood of murine tumor models and advanced cancer patients. We term these new structures circulating myeloid
cell (CMC) clusters. These observations led us to hypothesize that CMC clusters are an unrecognized functional
niche for systemic immune suppression in cancer. To test this hypothesis, we will first determine if blood-borne
MDSC target not only naïve T cells, but more broadly attack stem cell memory and central memory T cells and
natural killer cells that each require L-selectin for their antitumor activity. Secondly, we will determine if CMC
clusters are the active site of L-selectin cleavage by using a multipronged genetic approach to examine L-selectin
fate following disruption of MDSC-T cell conjugate formation in vivo. These mechanistic studies center on β2
integrins that are highly expressed by MDSC but are normally inactive on leukocytes in fast-flowing blood under
non-pathological conditions. Thirdly, we will examine the translational relevance of CMC clusters during ICI or
ACT therapy in a preclinical model in which blood is the primary effector site for MDSC due to their exclusion
from the TME (by blocking chemokine-directed trafficking) and spleen (by splenectomy). We will deplete
circulating MDSC in this model using antibodies or a clinically relevant liver-X-receptor agonist that induces
MDSC-intrinsic apoptosis to establish if blood-borne MDSC contribute to therapeutic resistance. Complementary
studies will test the hypothesis that combining the analysis of circulating MDSC with CMC clusters and/or T cell
L-selectin will formulate an immunosuppressive signature that predicts response to first-line therapy in metastatic
cancer patients. The proposed studies will provide new insights into an unprecedented function of circulating
myeloid cells and could lead to the consideration of CMC clusters as a functional biomarker for prognostication
or preselection of patients that would benefit from MDSC-depleting regimens during cancer immunotherapy.
使用免疫检查点抑制剂(ICI)或过继治疗的实体癌患者亚群的持久结果
细胞转移(ACT)免疫疗法引发了人们对更好地了解耐药性的兴趣
可以识别新的药物靶点的机制。骨髓源性抑制细胞 (MDSC)
基于其抑制先天免疫和适应性免疫的能力,它们成为了这样的屏障之一。血液升高的同时
MDSC被认为是癌症患者预后不良的指标,人们普遍认为其主要效应因子
MDSC 的位点位于肿瘤微环境 (TME) 内。这与有据可查的联系一致
涉及 T 细胞已知机制基础的短寿命中间体的依赖性机制
MDSC 抑制。我们发表的研究和初步研究放大了这一观点,表明 MDSC 还
通过前所未有的血管内免疫抑制机制在 TME 之外发挥作用。这
拟议的研究建立在我们发现循环 MDSC 启动 L-接触依赖性裂解的基础上
靶 T 细胞上的选择素归巢受体可显着减少抗原驱动的细胞毒性 T 细胞的扩增
在淋巴结中。我们进一步发现 L-选择素损失与稳定 MDSC 簇的形成相一致
小鼠肿瘤模型和晚期癌症患者的血液。我们将这些新结构称为循环骨髓
细胞(CMC)簇。这些观察结果使我们推测 CMC 簇是一种未被识别的功能
癌症全身免疫抑制的利基。为了检验这个假设,我们首先要确定是否是血源性的
MDSC 不仅针对幼稚 T 细胞,还更广泛地攻击干细胞记忆和中枢记忆 T 细胞,
每个自然杀伤细胞都需要 L-选择素来发挥其抗肿瘤活性。其次,我们将确定CMC是否
通过使用多管齐下的遗传方法来检查 L-选择素,簇是 L-选择素裂解的活性位点
体内 MDSC-T 细胞缀合物形成破坏后的命运。这些机制研究以β2为中心
整合素在 MDSC 中高度表达,但通常在快速流动的血液中的白细胞上不活跃。
非病理状况。第三,我们将检查 ICI 或 ICI 期间 CMC 簇的翻译相关性。
临床前模型中的 ACT 治疗,其中血液由于排除而成为 MDSC 的主要效应部位
来自 TME(通过阻断趋化因子定向运输)和脾脏(通过脾切除术)。我们将耗尽
在此模型中使用抗体或临床相关的肝脏 X 受体激动剂来诱导循环 MDSC
MDSC 内在细胞凋亡以确定血源性 MDSC 是否会导致治疗耐药。补充
研究将检验以下假设:将循环 MDSC 分析与 CMC 簇和/或 T 细胞相结合
L-选择素将形成免疫抑制特征,预测转移性一线治疗的反应
癌症患者。拟议的研究将为前所未有的循环功能提供新的见解
骨髓细胞,并可能导致考虑将 CMC 簇作为预测的功能性生物标志物
或预选在癌症免疫治疗期间受益于 MDSC 消耗方案的患者。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Scott I. Abrams其他文献
Differences in Immune Cell Populations between Individuals with or without MGUS
- DOI:
10.1182/blood-2024-206171 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Sawyer Bawek;Janine M. Joseph;Alan Hutson;Sarah Parker;Joseph D. Tario Jr;Hamza Hassan;Scott I. Abrams;Jens Hillengass - 通讯作者:
Jens Hillengass
Influence of interferon γ on modulation of Fas expression by human colon carcinoma cells and their subsequent sensitivity to antigen-specific CD8+ cytotoxic T lymphocyte attack
- DOI:
10.1007/s002620000105 - 发表时间:
2000-06-01 - 期刊:
- 影响因子:5.100
- 作者:
Elke S. Bergmann-Leitner;Scott I. Abrams - 通讯作者:
Scott I. Abrams
Immune response to a carcinoembryonic antigen polynucleotide vaccine.
对癌胚抗原多核苷酸疫苗的免疫反应。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:11.2
- 作者:
R. Conry;A. Lobuglio;Judy Kantor;Jeffrey Schlom;F. Loechel;S. Moore;L. Sumerel;D. L. Barlow;Scott I. Abrams;David T. Curici - 通讯作者:
David T. Curici
Immune Markers of Multiple Myeloma Patients Demonstrate Significant Change after Participation in Six-Month Physical Activity Intervention
- DOI:
10.1182/blood-2022-167655 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:
- 作者:
Janine M. Joseph;Michaela Hillengass;Hillary Jacobson;Joseph D. Tario;Kristopher Attwood;Adrienne Groman;Rikki Cannioto;Bryan Wittmeyer;Kirsten Moysich;Scott I. Abrams;Jens Hillengass - 通讯作者:
Jens Hillengass
Induction of antitumor immunity by recombinant vaccinia viruses expressing B7-1 or B7-2 costimulatory molecules.
通过表达 B7-1 或 B7-2 共刺激分子的重组痘苗病毒诱导抗肿瘤免疫。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:11.2
- 作者:
J. Hodge;Scott I. Abrams;J. Schlom;Judy Kantor - 通讯作者:
Judy Kantor
Scott I. Abrams的其他文献
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{{ truncateString('Scott I. Abrams', 18)}}的其他基金
Development of a Novel Immunotherapy Platform for Triple-Negative Breast Cancer
开发针对三阴性乳腺癌的新型免疫治疗平台
- 批准号:
10463811 - 财政年份:2021
- 资助金额:
$ 69.42万 - 项目类别:
Development of a Novel Immunotherapy Platform for Triple-Negative Breast Cancer
开发针对三阴性乳腺癌的新型免疫治疗平台
- 批准号:
10287834 - 财政年份:2021
- 资助金额:
$ 69.42万 - 项目类别:
Impact of Circulating Myeloid Cell Clusters on Anti-Tumor Immunity
循环骨髓细胞簇对抗肿瘤免疫的影响
- 批准号:
10543820 - 财政年份:2021
- 资助金额:
$ 69.42万 - 项目类别:
Tumor Immune Contexture and Breast Cancer Disparities: A Multi-Disciplinary Study in Women of African and European Ancestry
肿瘤免疫环境和乳腺癌差异:针对非洲和欧洲血统女性的多学科研究
- 批准号:
10653186 - 财政年份:2020
- 资助金额:
$ 69.42万 - 项目类别:
Tumor Immune Contexture and Breast Cancer Disparities: A Multi-Disciplinary Study in Women of African and European Ancestry
肿瘤免疫环境和乳腺癌差异:针对非洲和欧洲血统女性的多学科研究
- 批准号:
10171569 - 财政年份:2020
- 资助金额:
$ 69.42万 - 项目类别:
Tumor Immune Contexture and Breast Cancer Disparities: A Multi-Disciplinary Study in Women of African and European Ancestry
肿瘤免疫环境和乳腺癌差异:针对非洲和欧洲血统女性的多学科研究
- 批准号:
10404988 - 财政年份:2020
- 资助金额:
$ 69.42万 - 项目类别:
A Cobalt Porphyrin Nanoliposome Adjuvant for MHC-I-Restricted Cancer Peptide Vaccines
用于 MHC-I 限制性癌症肽疫苗的钴卟啉纳米脂质体佐剂
- 批准号:
10320831 - 财政年份:2020
- 资助金额:
$ 69.42万 - 项目类别:
A Cobalt Porphyrin Nanoliposome Adjuvant for MHC-I-Restricted Cancer Peptide Vaccines
用于 MHC-I 限制性癌症肽疫苗的钴卟啉纳米脂质体佐剂
- 批准号:
10557071 - 财政年份:2020
- 资助金额:
$ 69.42万 - 项目类别:
Multidisciplinary Approaches to Tumor Immunology
肿瘤免疫学的多学科方法
- 批准号:
10248383 - 财政年份:2019
- 资助金额:
$ 69.42万 - 项目类别:
Multidisciplinary Approaches to Tumor Immunology
肿瘤免疫学的多学科方法
- 批准号:
10472619 - 财政年份:2019
- 资助金额:
$ 69.42万 - 项目类别:
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