Immunosuppression and Metabolic Rewiring in Tumor-infiltrating Neutrophils
肿瘤浸润中性粒细胞的免疫抑制和代谢重组
基本信息
- 批准号:10637160
- 负责人:
- 金额:$ 36.2万
- 依托单位:
- 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:2023-05-01 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAccelerationAconitic AcidAddressAnti-Inflammatory AgentsAntibodiesAntioxidantsB-LymphocytesBiological AssayBreast Cancer ModelBreast Cancer TreatmentBreast cancer metastasisCarboxy-LyasesCell modelCellsClinicalCytotoxic T-LymphocytesDevelopmentEnsureEnzymesFaceGene SilencingGenesGoalsGranulocyte-Macrophage Colony-Stimulating FactorHumanImmuneImmune EvasionImmunofluorescence ImmunologicImmunosuppressionImmunotherapeutic agentImmunotherapyIn VitroInfiltrationInjectionsJAK2 geneKnockout MiceKnowledgeLinkLungMacrophageMalignant NeoplasmsMammary NeoplasmsMediatingMetabolicMetastatic Neoplasm to the LungMetastatic breast cancerMitochondriaModelingMolecularMorbidity - disease rateMouse Mammary Tumor VirusMusMyeloid-derived suppressor cellsNeoplasm MetastasisNeutrophil InfiltrationOutcomePathway interactionsPatientsPhenotypePopulationProductionPrognosisResearchResistanceRoleSTAT3 geneSafetySamplingStainsT cell infiltrationT-LymphocyteTechniquesTestingTherapeuticTissue MicroarrayTransgenic MiceTumor ImmunityUp-RegulationValidationWild Type Mousebench-to-bedside translationbonecancer immunotherapychemotherapycurative treatmentsdeprivationexperimental studyfollow-upimmune checkpoint blockadeimmune resistanceimmunoregulationimprovedinhibitorloss of functionmalignant breast neoplasmmortalitymouse modelneutrophilnew therapeutic targetnovelpharmacologicpolyoma middle tumor antigenpre-clinicalprogrammed cell death ligand 1programsresponsesingle cell technologysingle-cell RNA sequencingsynergismtherapeutic targettriple-negative invasive breast carcinomatumortumor microenvironmentvalidation studies
项目摘要
PROJECT SUMMARY/ABSTRACT
Metastatic breast cancer (BC) remains largely resistant to immune checkpoint blockade (ICB) therapy.
Tumor-infiltrating neutrophils (TINs) with immunosuppressive activity represent a major component in the tumor
microenvironment (TME) to drive immunotherapy resistance. Therapeutic debilitation of immunosuppressive
TINs is a promising approach to elicit synergistic efficacy when combined with immunotherapy. However,
therapeutic targeting of TINs faces challenges in selectivity and safety, highlighted by the lack of TIN-specific
targets. Recently, we used single-cell RNA sequencing to compare TINs and circulating neutrophils in BC models
and identified aconitate decarboxylase 1 (Acod1) to be uniquely upregulated in TINs. Acod1 catalyzes the
production of itaconate, a metabolite with anti-inflammatory activity in macrophages. But Acod1 function in
neutrophils is poorly defined. Our preliminary results in BC mouse models suggest that TINs rely on Acod1 to
sustain survival in the TME, and Acod1 loss leads to reduced TIN infiltration and metastasis. There are still
significant knowledge gaps about the function, mechanism and therapeutic potential of Acod1 in TINs.
Our central hypothesis is that Acod1 upregulated in TINs that infiltrate metastatic BC is essential for the
TINs to persist in the TME and exert the immunosuppressive function, thus Acod1 ablation debilitates TINs,
favors anti-tumor immunity, and sensitizes metastatic BC to immunotherapy. We propose to accomplish three
Specific Aims: (Aim 1) Validate the pro-metastasis function of Acod1 in TINs in syngeneic and spontaneous
murine mammary tumor models. (Aim 2) Identify the upstream and downstream molecular mechanisms
underlying the upregulation and function of Acod1 in TINs. (Aim 3) Improve metastatic BC response to
immunotherapy by Acod1 ablation and validate ACOD1 expression in clinical samples.
To achieve our research goals, we have developed both whole-body and neutrophil-specific Acod1
knockout mice as hosts for BC syngeneic models, both mouse and human in vitro cell models of TINs, single-
cell technologies for gene profiling and immune cell phenotyping, injection techniques that generate mammary
tumors and metastases to lung and bone in the mice, and multiplex immunofluorescence staining techniques
suitable for validation studies using clinical samples. We have assembled a strong research team with
complementary expertise, which further ensures that the studies proposed are highly feasible to accomplish.
Upon completion of the project, we expect to uncover the previous unknown function and mechanism of
Acod1 in immunosuppressive TINs that are enriched in BC metastases, provide novel links between metabolic
rewiring and immunoregulatory function of TINs, and generate the key preclinical evidence for targeting Acod1
to improve immunotherapy. In the long term, we envision that the bench-to-bedside translation of our findings
through development of Acod1 inhibitors may accelerate the therapeutic application of combining agents that
reprogram immunometabolism and immunotherapeutics to the curative treatment of BC and other cancers.
项目总结/文摘
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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Xin Lu其他文献
Xin Lu的其他文献
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{{ truncateString('Xin Lu', 18)}}的其他基金
Converting Cold to Hot Tumor Microenvironment in Prostate Cancer by Targeting Chromatin Effector
通过靶向染色质效应器将前列腺癌中的冷肿瘤微环境转变为热肿瘤微环境
- 批准号:
10395485 - 财政年份:2020
- 资助金额:
$ 36.2万 - 项目类别:
Converting Cold to Hot Tumor Microenvironment in Prostate Cancer by Targeting Chromatin Effector
通过靶向染色质效应器将前列腺癌中的冷肿瘤微环境转变为热肿瘤微环境
- 批准号:
10600114 - 财政年份:2020
- 资助金额:
$ 36.2万 - 项目类别:
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