In Situ characterization and manipulation of tumor immune cell metabolomics using implantable microdevices

使用植入式微装置对肿瘤免疫细胞代谢组学进行原位表征和操作

• 批准号: 10436814
• 负责人: Oliver Jonas
• 金额: $ 38.64万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436814
• 关键词: Address; Affect; Antineoplastic Agents; Architecture; Biological; Biological Products; Cells; Chemicals; Clinical; Development; Generations; Glucose; Glutamine; Immune; Immune checkpoint inhibitor; Immunologics; Immunotherapy; In Situ; Isotope Labeling; Lead; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measurement; Metabolic; Metabolism; Minority; Molecular Probes; Nutrient; Organ; Patients; Population; Process; Resolution; Stable Isotope Labeling; Techniques; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tissue imaging; Tumor-infiltrating immune cells; cancer immunotherapy; cancer therapy; cell type; chemokine; chemotherapy; cytokine; cytotoxic; insight; metabolic profile; metabolomics; microdevice; neoplastic cell; novel; novel strategies; patient response; personalized immunotherapy; response; success; tumor; tumor metabolism; tumor microenvironment

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. !

文摘: