Gasdermin E-mediated pyroptosis in promoting antitumor immunity and cancer treatment
Gasdermin E-mediated pyroptosis in promoting antitumor immunity and cancer treatment
批准号:
10338167
负责人:
Ying Zhang
金额:
$11.22万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-02-01 至 2022-06-30
关键词:
AddressAffectAntibodiesAntigensApoptosisBioinformaticsBlocking AntibodiesBone MarrowCASP3 geneCD8-Positive T-LymphocytesCD8B1 geneCancer PatientCaspaseCell Culture TechniquesCell DeathCell MaturationCell physiologyChemicalsCollaborationsCommunitiesCross PresentationCytometryCytotoxic agentDNA MethylationDNA Modification MethylasesDecitabineDendritic CellsDendritic cell tumorDrug TargetingEffectivenessEnzymesFDA approvedFlow CytometryGoalsHypermethylationImmuneImmune responseImmunityImmuno-ChemotherapyImmunologicsImmunotherapeutic agentImmunotherapyInflammatoryInjectionsInvestigationLaboratoriesLeadLymphocyteLyticMalignant NeoplasmsMediatingMediator of activation proteinMemoryMentorsModelingMolecularMusN-terminalPatientsPatternPhagocytesPharmaceutical PreparationsPhasePlayProductionPropertyProtein KinaseProteinsRIPK1 geneResearchResearch PersonnelResourcesRoleSeriesShapesStressT cell responseT-LymphocyteT-cell inflamedTechnologyTestingTherapeuticTimeTissuesTrainingTransgenic MiceTranslational ResearchTumor ImmunityTumor-Infiltrating LymphocytesTumor-associated macrophagesTumor-infiltrating immune cellsVDAC1 geneWorkantitumor effectcancer cellcancer immunotherapycancer therapycareerchemokinecytokinecytotoxicepigenetic silencingexpectationimmunoregulationimprovedinhibitormouse modelneoplastic cellnovel strategiesnovel therapeuticspromoterreceptorrecruitresponsesingle-cell RNA sequencingskillstumortumor growthtumor immunologytumor microenvironment
中文摘要
项目总结/文摘
英文摘要
Project Summary/Abstract
The majority of cancers, which are immunologically “cold” with limited T cell infiltration, show abysmal response
rates to immunotherapy. Novel strategies to enhance recruitment and functions of tumor-infiltrating lymphocytes
(TIL) are urgently needed to improve cancer immunotherapy. How cancer cells die in response to stress,
cytotoxic lymphocytes, and drugs has a profound impact on the immune landscape of cancer. While most cancer
cell death has been viewed as noninflammatory, our recent study showed that pore-forming protein Gasdermin
E (GSDME), when expressed in tumor cells, converts noninflammatory apoptosis to pyroptosis, a highly
inflammatory form of programmed cell death. GSDME potently inhibits tumor growth and enhances the numbers
and antitumor functions of CD8+ and NK TILs. The tumor-inhibitory effect of GSDME is mediated by TIL killing
of GSDME+ target tumor cells, which can also trigger tumor cell pyroptosis. Our study suggests that promoting
cancer cell pyroptosis has excellent potential to improve cancer immunotherapy, but it remains unclear how
GSDME-induced pyroptosis boosts antitumor immunity. The proposed research aims to investigate how tumor
GSDME expression shapes the tumor-infiltrating immune cells and their interactions to increase tumor immunity,
and to develop a novel strategy to promote inflammatory cancer cell death, with the long-term goal to enhance
immunotherapeutic efficacy for cancer patients. Specifically, I will study how damage-associated molecular
patterns (DAMPs) produced by GSDME+ tumor cells modulate the composition, maturation, and functions of
tumor-infiltrating dendritic cells (TIDCs) and tumor-associated macrophages (TAMs), key players to induce
potent antitumor T cell response, by using CyTOF and inhibitors of DAMPs or their receptors (Aim 1). Aided by
single cell (sc)RNA-seq and bone marrow chimeric mice, I will study how different TIDC subsets interact with
CD8+ TILs to promote GSDME-mediated antitumor immunity (Aim 2). As many cancer cells epigenetically silence
GSDME and RIPK3 (key mediator of necroptosis, another inflammatory form of cell death) via promoter
hypermethylation, I will investigate whether the DNA methylation inhibitor decitabine could promote cancer cell
pyroptosis and necroptosis to suppress tumor growth and enhance antitumor immunity (Aim 3). These studies
will greatly advance our understanding of GSDME’s immunostimulatory mechanism and offer new opportunities
to revitalizing immunotherapeutic efficacy for patients with uninflamed “cold” tumors. My career goal is to lead
an independent academic laboratory addressing questions on cancer immunology and immunotherapy. In the
K99 phase, I will take full advantage of the extensive resources at the vibrant research community of Harvard
and the outstanding team of mentors and collaborators to receive comprehensive training in advanced
technologies, bioinformatics, mouse models, and translational research, to further establish collaborations and
sharpen my professional skills. The proposed training plan will serve as a superb roadmap that will lead me to
my goal of succeeding as an independent investigator, and to make a difference in the lives of cancer patients.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1158/2326-6066.cir-20-0525
发表时间:
2021-01
期刊:
Cancer immunology research
影响因子:
10.1
作者:
[Zhang Z, Zhang Y, Lieberman J]
通讯作者:
Lieberman J
STRONG HEART STUDY (SHS)- OKLAHOMA UNIVERSITY HEALTH CENTER (OUHSC) COORDINATING CENTER(CC) SUBTASK B.2 - PHASE VII EXAM AND EXAM CLOSEOUT.
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批准号:10973980
-
项目类别:
-
资助金额:$127.08万
-
财政年份:2022
-
负责人:Ying Zhang
-
依托单位:
Biostatistics, Epidemiology, and Research Design Core
-
批准号:10478949
-
项目类别:
-
资助金额:$33.12万
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财政年份:2016
-
负责人:Ying Zhang
-
依托单位:
Biostatistics, Epidemiology, and Research Design Core
-
批准号:10281658
-
项目类别:
-
资助金额:$33.01万
-
财政年份:2016
-
负责人:Ying Zhang
-
依托单位:
海外基金