A new mouse model for studying the pathogenesis and immunobiology of intrahepatic cholangiocarcinoma and improving its immunotherapy
A new mouse model for studying the pathogenesis and immunobiology of intrahepatic cholangiocarcinoma and improving its immunotherapy
批准号:
10711615
负责人:
Michael Karin
金额:
$56.39万
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:
2023-09-19 至 2028-08-31
关键词:
AccountingAlcohol abuseBiliaryCD8-Positive T-LymphocytesCell CommunicationCell NucleusCell Surface ReceptorsCellsCharacteristicsCholestasisClinicalClinical ManagementComplementComplicationDataDesmoplasticDiagnosisDifferential DiagnosisEarly DiagnosisEpigenetic ProcessEvaluationEvolutionExclusionExhibitsFailureFibroblastsGoalsHepatobiliaryHepatocyteHigh Fat DietHumanImmuneImmune checkpoint inhibitorImmunobiologyImmunocompetentImmunophenotypingImmunosuppressionImmunotherapyIncidenceInflammatory Bowel DiseasesIntraepithelial NeoplasiaIntrahepatic CholangiocarcinomaKDR geneLesionMalignant - descriptorMalignant NeoplasmsMapsMediatingModelingMolecularMusMutationMyeloid-derived suppressor cellsNoduleNon-Insulin-Dependent Diabetes MellitusOncogenicPathogenesisPathologicPrimary Malignant Neoplasm of LiverPrimary carcinoma of the liver cellsRadiology SpecialtyReactionRisk FactorsSignal TransductionStudy modelsSurvival RateT cell receptor repertoire sequencingT-LymphocyteT-cell receptor repertoireTechniquesTherapeuticTranscriptional ActivationTranslatingTumor-Infiltrating LymphocytesVariantVegf Inhibitorbiliary tractcancer cellcancer typecheckpoint inhibitioncholangiocyteendoplasmic reticulum stressexperimental studyimmunogenicimprovedinformation gatheringinhibitormouse modelneoplasticnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnoveloverexpressionpressurepreventprogenitorregenerativeresponsetobacco abusetranscription factortranscriptomicstumortumor microenvironmenttumor-immune system interactions
中文摘要
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英文摘要
ABSTRACT
Intrahepatic cholangiocarcinoma (ICC) is an aggressive primary liver cancer (PLC) that is particularly hard to
treat, having an overall 5-year survival rate of 8%. Like the major PLC, hepatocellular carcinoma (HCC), ICC
incidence is on the rise due to the ongoing increase in cholestatic liver diseases, non-alcoholic fatty liver diseases,
type 2 diabetes and alcohol and tobacco abuse. Unlike HCC, ICC is often detected at an advanced stage when
survival prospects are poor, a complication of its imprecise differentiation from early HCC by current radiological
techniques. Early differential diagnosis of two PLCs is critical due to their distinct management and the absence
of targetable oncogenic drivers shared by ICC and HCC. This problem could be solved by identification of a PLC-
type agnostic therapeutic approach, such as immune checkpoint inhibition (ICI), that is applicable to both ICC
and HCC. However, while ICI based therapies were approved for HCC and their efficacy has been improved by
combination with VEGF inhibitors, they have performed poorly in ICC. This failure can be attributed, in part, to
poor mechanistic understanding of the ICC-specific immunosuppressive tumor microenvironment (TME) and
lack of suitable mouse models that allow the evaluation of ICI in combination with therapeutics capable of
dismantling immunosuppression. We have solved this problem by developing a new ICC model that unlike
previous mouse models does not depend on forced overexpression of potent oncogenic drivers that rapidly
induce ICC in the absence of selective pressure for acquisition of additional mutations. Our MUP-uPA/NRF2Act
model depends on combination of ER stress with activation of transcription factor NRF2 in bipotential
hepatobiliary progenitors and mature hepatocytes and shows robust, highly penetrant, human-like stepwise
progression towards ICC that is accompanied by the buildup of an immunosuppressive TME exhibiting CD8+ T
cell exclusion. We plan to establish the MUP-uPA/NRF2Act mouse as the leading model for studying the evolution
of ICC and its immunosuppressive TME and for finding treatments that will dismantle immunosuppression and
boost the response to existing PD-(L)1 inhibitors. To accomplish this goal, we will fully characterize the MUP-
uPA/NRF2Act mouse, defining the transcriptomic, epigenetic, and genetic alterations at each stage of ICC
progression, including ductular reactions, biliary intraepithelial neoplasia and established desmoplastic cancer.
We will also define the T cell receptor (TCR) repertoire of tumor infiltrating lymphocytes at each stage of
malignant progression and mine the transcriptomic data for cancer cell produced factors that mediate
desmoplasia, immunosuppression and CD8+ T cell exclusion. These studies will be complemented by
immunophenotyping and immunodepletion experiments whose goal is the identification of targetable molecular
switches responsible for establishment of the ICC-specific immunosuppressive TME. We will use this information
to identify clinically approved treatments that can overcome immunosuppression and vastly improve the efficacy
of ICI therapy based on PD-(L)1 inhibitors.
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