Immune Aging in Responsiveness to Checkpoint Blockade Immunotherapies
Immune Aging in Responsiveness to Checkpoint Blockade Immunotherapies
批准号:
10674256
负责人:
Vandana Kalia
金额:
$40.36万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-09-02 至 2024-08-31
关键词:
Adoptive TransferAgeAgingAgonistAntibodiesAntigen-Antibody ComplexAntitumor ResponseAtrophicBiochemicalBlocking AntibodiesCD8-Positive T-LymphocytesCaloric RestrictionCancerousCell CountCellsChronicClinicClinicalCytotoxic T-LymphocytesDataDefectDevelopmentDiagnosisDiseaseDominant-Negative MutationElderlyFDA approvedFRAP1 geneGoalsHIVHepatitis C virusHumanImmuneImmune TargetingImmune responseImmune systemImmunityImmunizationImmunologic MarkersImmunologicsImmunosuppressionImmunotherapeutic agentImmunotherapyImpairmentInfectionInterleukin-2KnowledgeLaboratoriesMalignant NeoplasmsMediatingMedical HistoryMemoryMetabolicMetabolic PathwayMitochondriaMolecularMusMutationNon-Small-Cell Lung CarcinomaOutcomeOutcome StudyOutputPathway interactionsPatientsPeripheralPharmacologyPhysiologicalPredispositionProductionPublic HealthRefractoryRegulationRegulatory T-LymphocyteRejuvenationReportingRoleSEER ProgramSeveritiesSignal PathwaySignal TransductionSirolimusSolid NeoplasmT cell responseT-LymphocyteT-Lymphocyte SubsetsTCF Transcription FactorTestingThymectomyThymus GlandTranslatingTreatment EfficacyTumor ImmunityVaccinesWomanage effectage relatedagedanti-PD-1anti-PD1 therapybasecancer immunotherapycheckpoint therapychronic infectionclinical efficacycytotoxicdietaryexhaustexhaustionimmune checkpoint blockadeimmune functionimprovedinsightinterestmelanomamenmetermitochondrial metabolismneoantigensneoplasm immunotherapynovelnovel strategiesoverexpressionpatient responsepredictive markerprogrammed cell death protein 1receptorrecruitrestraintstatisticsstemsuccesstherapy outcomethymocytetooltumortumor microenvironmenttumor progressionvaccine efficacy
中文摘要
衰老对免疫有深远的影响(免疫老化),有报道说更容易
英文摘要
Aging has a profound influence on immunity (Immune aging), with reports of greater susceptibility to
cancers and infections, lower vaccine efficacy, and weakened immunity against persistent infections with
advancing age. Nonetheless, surprisingly little is known about how cancer immunity and immunotherapy
outcomes are altered with immune aging.
The SEER program (Surveillance Epidemiology End Result, https://seer.cancer.gov) estimates approximately
38.4 percent of men and women will be diagnosed with cancer at some point during their lifetime. In the face of
these alarming statistics, last decade has heralded remarkable new immune-based therapies with potent clinical
efficacy. A frontline FDA-approved therapy - checkpoint blockade immunotherapy (CBI) using antibodies that
block a dominant negative regulator of T cell responses, PD-1 or PD-L 1 - has proven to be a real tour de force
in treating several refractory solid tumors (such as RCC, NSCLC, MCC and melanoma). However, not all patients
respond to PD-1 CBI, the degree of responsiveness is variable, and the biomarkers predictive of therapeutic
efficacy remain largely elusive. The goal of this project is to unravel the immunometabolic mechanisms
underlying the widely disparate efficacy of PD-1 CBI, with "immune aging".
Based on several documented immune defects with age, we predicted that therapeutic efficacy of PD-1 CBI
might be compromised with advancing age. Indeed, recent studies from our laboratory and others' demonstrate
impaired responsiveness to PD-1 CBI in aged versus young hosts. Mechanistically, tantalizing new data show
that CD8 T cells that respond most efficiently to PD-1 CBI are newly (or less) exhausted by virtue of being
recently recruited into the immune response. Since na"ive CD8 T cell numbers, repertoire and function decline
with age (due to the combined result of developmentally-programmed thymic atrophy and past medical history),
we propose that immune aging-related decline in na·ive CD8 T cell quantity and quality leads to a reduction in
the pool of less exhausted tumor-reactive CD8 T cells more amenable to functional rescue, thus compromising
the efficacy of PD-1 checkpoint blockade therapy. The goal of this proposal is to understand how immune aging
related decline in na"ive CD8 T cell repertoire and/or metabolic function impacts the extent of exhaustion and
therapeutic efficacy of PD-1 CBI. We further aim to define the metabolic determinants of T cell rejuvenation
potential - as regulated by age-related alterations in T cell exhaustion - and evaluate novel strategies to
potentially augment the therapeutic efficacy of PD-1 CBI by promoting the development of less exhausted cells
that are more responsive to CBI through alterations in na·ive T cell thymic output, activation, expansion or
cytotoxic function. By elucidating immune aging-related mechanisms of T cell exhaustion that influence therapy
outcomes, these studies will provide insight into the disparity in patient responsiveness, and will offer novel
strategies to augment therapeutic efficacy.
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