In Situ characterization and manipulation of tumor immune cell metabolomics using implantable microdevices
In Situ characterization and manipulation of tumor immune cell metabolomics using implantable microdevices
批准号:
10436814
负责人:
Oliver Jonas
金额:
$38.64万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-07-01 至 2024-06-30
关键词:
AddressAffectAntineoplastic AgentsArchitectureBiologicalBiological ProductsCellsChemicalsClinicalDevelopmentGenerationsGlucoseGlutamineImmuneImmune checkpoint inhibitorImmunologicsImmunotherapyIn SituIsotope LabelingLeadMalignant NeoplasmsMapsMass Spectrum AnalysisMeasurementMetabolicMetabolismMinorityMolecular ProbesNutrientOrganPatientsPopulationProcessResolutionStable Isotope LabelingTechniquesTestingTherapeuticTherapeutic AgentsTherapeutic InterventionTissue imagingTumor-infiltrating immune cellscancer immunotherapycancer therapycell typechemokinechemotherapycytokinecytotoxicinsightmetabolic profilemetabolomicsmicrodeviceneoplastic cellnovelnovel strategiespatient responsepersonalized immunotherapyresponsesuccesstumortumor metabolismtumor microenvironment
中文摘要
文摘:
英文摘要
Abstract:
Immunotherapy holds great therapeutic promise across many cancer indications, but currently
only a minority of patients receiving it show durable responses. The interplay between immune
cells and tumor cells is a critical determinant of the efficacy of immunotherapy. Both cell
populations are high consumers of energy, and understanding the metabolomic processes in
cancer and immune cells within the tumor microenvironment is regarded as central to increasing
the clinical success of immunotherapies.
This proposal describes a novel technological approach to examine the metabolomics of immune
cells within a tumor. We employ implantable microdevices that allow us to selectively attract
immune cells and locally probe their response to many different therapeutic and biological
agents, including checkpoint inhibitors, cytokines and chemokines, modulators of metabolic
activity, and anti-cancer agents. The resulting intratumor regions of enriched immune cell
populations are profiled for 400+ metabolites using mass spectrometry tissue imaging, providing
quantitative relationships between each metabolite and the proliferation and anti-tumor activity of
the immune cells – all within the native tumor microenvironment.
Furthermore, this platform will be employed to directly track the metabolic competition between
immune and tumor cells, of glucose and glutamine in the live tumor through isotope labeling.
Direct, high-throughput in-situ hypothesis testing is performed to systemically address how a
large set of immune, cytotoxic and metabolic modulators reprogram the metabolic profile of
various cell types in the tumor to favor the anti-tumor activity of immune cells.
The blend of chemical and biological perturbation directly in the native tumor microenvironment,
performed by the microdevice in a high-throughput manner, with mass spectrometry tissue
imaging to obtain comprehensive metabolomic snapshots, represents a new paradigm for
discerning the relationship between the metabolism and anti-tumor activity of immune cells in
tumors. We anticipate this project to yield novel mechanistic insight that may lead to the
enhancement and personalization of immunotherapy, and its combination with chemotherapy, to
obtain more durable patient responses in a variety of cancers.
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依托单位:
海外基金