Sexual Dimorphism in T Cell Exhaustion and Bladder Cancer
Sexual Dimorphism in T Cell Exhaustion and Bladder Cancer
批准号:
10629078
负责人:
Zihai Li
金额:
$53.14万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-06-01 至 2028-05-31
关键词:
AdoptedAggressive behaviorAndrogen ReceptorAndrogensAntitumor ResponseBiologicalCD8-Positive T-LymphocytesCD8B1 geneCancer ModelCell ProliferationCell SurvivalCellular biologyChromosomesChronicCollaborationsDataEnvironmentEpigenetic ProcessFemaleFrequenciesFunctional disorderGenesGenetic TranscriptionGoalsGonadal Steroid HormonesHormonesImmuneImmune EvasionImmune responseImmunityImmunologicsImmunologyImmunotherapyIn VitroIncidenceKnowledgeLinkMalignant NeoplasmsMalignant neoplasm of urinary bladderMediatingMolecularMolecular TargetMusOrganPopulationProductionPrognosisProteinsPublishingReceptor SignalingRejuvenationReportingRisk FactorsRoleScienceSex BiasSex ChromosomesSex DifferencesSignal TransductionSmokingT cell differentiationT cell responseT-Cell ReceptorT-LymphocyteTumor-Infiltrating LymphocytesWomanWorkZinc Fingersandrogen deprivation therapyanti-PD-1anti-PD1 therapycancer immunotherapycancer subtypescell typechromosome Y losseffector T cellexhaustexhaustiongene networkimmune checkpoint blockadeimmune functionimprovedin vivomalemennuclear factors of activated T-cellsprogenitorprogramsresponsesexsexual dimorphismsingle-cell RNA sequencingtranscription factortumortumor microenvironmenttumor progression
中文摘要
项目1 -总结
英文摘要
PROJECT 1 – SUMMARY
Sex is an understudied biological variable with significant influence on immune function, including in the context
of cancer. However, the immunological mechanisms underlying the sex bias seen in cancers from non-
reproductive organs, such as bladder cancer (BC), remain elusive. Male bias in BC incidence persists after
adjustment for other known risk factors suggesting a fundamental biological basis for this sexual dimorphism.
Objective: To define the molecular mechanisms by which androgens, AR target genes, and sex chromosome-
encoded epigenetic modifiers contribute to sex differences in CD8+ T cell exhaustion in the tumor
microenvironment (TME). Impact: Our study will uncover an immunological basis and mechanism by which
CD8+ T cell exhaustion contributes to sex bias in BC, with implications for improving ICB approaches for all
cancer via three specific aims. Aim 1: Determine the role of AR-TCF1 and AR-TOX in CD8+ T cell exhaustion
and tumor control. The molecular mechanisms by which androgens influence T cells and contribute to cancer
progression are unclear. Male CD8+ tumor-infiltrating lymphocytes (TILs) preferentially adopt a TCF1+ PE state
due to direct activation of Tcf7 by AR. Hypothesis. Androgen signaling establishes a stable TCF1-driven
transcriptional network in CD8+ T cells that favors exhaustion, through the modulation of TOX, another critical
transcription factor (TF) that promotes T cell exhaustion. Aim 2: Determine the role of AR-ZFP148 in T cell
effector differentiation. TF ZFP148 regulates cell proliferation and survival in non-immune cell types but has
not been studied in T cell biology. Single-cell RNA-seq analyses demonstrated male-biased Zfp148 expression
and regulatory activity in PE CD8+ T cells stimulated by AR. T cell receptor (TCR) engagement and chronic
exhaustion induced Zfp148 expression in CD8+ T cells, and its deletion led to better effector function in vitro. The
in vivo persistence of Zfp148 null T cells was compromised. Hypothesis. AR-regulated ZFP148 can suppress
CD8+ T cell effector function and contributes to male-biased BC. Aim 3: Investigate the role of AR and
epigenetic modifiers in CD8+ T cell exhaustion and tumor response to immunotherapy. The impact of sex
chromosome-encoded epigenetic modifiers in BC – including KDM5D, UTY, and KDM6A – on immunity
especially in the CD8+ compartment is a major gap in the field. In collaboration with Project 2, we found that loss
of the Y chromosome (LOY) (especially the genes Kdm5d and Uty) contributes to CD8+ T cell exhaustion in BC.
Hypothesis. Sex hormones and sex chromosome-encoded epigenetic modifiers contribute to CD8+ T cell
exhaustion and BC sensitivity to ICB.
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科研奖励(0)
会议论文
Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy Supplement
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批准号:10818173
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项目类别:
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资助金额:$7.21万
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财政年份:2021
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负责人:Zihai Li
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依托单位:
Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy
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批准号:10474548
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项目类别:
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资助金额:$59.43万
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财政年份:2021
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负责人:Zihai Li
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依托单位:
Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy
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批准号:10689068
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项目类别:
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资助金额:$53.79万
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财政年份:2021
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依托单位:
Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy
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批准号:10275810
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项目类别:
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资助金额:$56.92万
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财政年份:2021
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依托单位:
Integration of inflammation and cancer by molecular chaperone
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批准号:10056559
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资助金额:$16.12万
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财政年份:2017
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负责人:Zihai Li
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依托单位:
Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy
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批准号:9321008
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项目类别:
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资助金额:$133.53万
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财政年份:2015
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负责人:Zihai Li
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依托单位:
Project 1: Definition of grp94-GARP-TGFbeta Axis in Cancer Biology and Clinical Significance
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批准号:8934513
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项目类别:
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资助金额:$22.38万
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财政年份:2015
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负责人:Zihai Li
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依托单位:
Novel mechanisms of UPR sensing and nonalcoholic fatty liver disease
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批准号:9026108
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项目类别:
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资助金额:$33.64万
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财政年份:2015
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负责人:Zihai Li
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依托单位:
Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy
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批准号:8934510
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项目类别:
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资助金额:$133.75万
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财政年份:2015
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负责人:Zihai Li
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依托单位:
Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy
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批准号:9770790
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项目类别:
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资助金额:$135.49万
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财政年份:2015
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负责人:Zihai Li
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依托单位:
Thrombocytes in Cancer Immunity
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批准号:9235264
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项目类别:
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资助金额:$38.72万
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财政年份:2015
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负责人:Zihai Li
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依托单位:
Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy
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批准号:9135256
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项目类别:
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资助金额:$138.52万
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财政年份:2015
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负责人:Zihai Li
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依托单位:
Novel mechanisms of UPR sensing and nonalcoholic fatty liver disease
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批准号:9190367
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项目类别:
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资助金额:$33.64万
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财政年份:2015
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负责人:Zihai Li
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依托单位:
Thrombocytes in Cancer Immunity
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批准号:10047658
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项目类别:
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资助金额:$22.51万
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财政年份:2015
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负责人:Zihai Li
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依托单位:
Novel Chaperone Mechanism for Platelet Disorder
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批准号:7934003
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项目类别:
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资助金额:$50.0万
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财政年份:2009
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负责人:Zihai Li
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依托单位:
Molecular chaperones and immune tolerance
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批准号:9440331
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项目类别:
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资助金额:$37.38万
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财政年份:2009
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负责人:Zihai Li
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依托单位:
gp96, TLR and immunologic tolerance
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批准号:8091738
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项目类别:
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资助金额:$36.51万
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财政年份:2009
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负责人:Zihai Li
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依托单位:
Molecular chaperones and immune tolerance
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批准号:9310818
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项目类别:
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资助金额:$37.38万
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财政年份:2009
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负责人:Zihai Li
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依托单位:
gp96, TLR and immunologic tolerance
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批准号:8029526
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项目类别:
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资助金额:$36.14万
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财政年份:2009
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负责人:Zihai Li
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依托单位:
Molecular chaperones and immune tolerance
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批准号:10112807
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项目类别:
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资助金额:$38.75万
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财政年份:2009
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负责人:Zihai Li
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依托单位:
海外基金