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

基本信息

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
项目类别：
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

项目摘要

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. !

抽象的：免疫疗法在许多癌症的适应症中都具有巨大的治疗前景，但目前只有少数接受IT的患者显示出持久的反应。免疫之间的相互作用细胞和肿瘤细胞是免疫疗法效率的关键确定剂。两个细胞人群是能量的高消费者，并且了解代谢组的过程肿瘤微环境中的癌症和免疫细胞被认为是增加免疫疗法的临床成功。该建议描述了一种研究免疫代谢组学的新型技术方法细胞内的肿瘤。我们采用可植入的微型版本，使我们能够选择性地吸引免疫细胞并局部探测它们对许多不同治疗和生物学的反应药物，包括检查点抑制剂，细胞因子和趋化因子，代谢的调节剂活动和抗癌药。富集的免疫球的肿瘤内区域使用质谱组织成像为400多种代谢产物进行了构图，提供每种代谢物与增殖和抗肿瘤活性之间的定量关系免疫细胞 - 全部在天然肿瘤微环境中。此外，该平台将被雇用以直接跟踪免疫细胞和肿瘤细胞，通过同位素标记在活肿瘤中的葡萄糖和谷氨酰胺的。进行直接，高通量的原位假设检验，以系统地解决如何解决大型免疫，细胞毒性和代谢调节剂重编程肿瘤中的各种细胞类型有利于免疫细胞的抗肿瘤活性。直接在天然肿瘤微环境中的化学和生物扰动的混合物，通过质谱组织以高通量方式通过微电位进行的成像以获得全面的代谢组分快照，代表了一个新的范式辨别免疫球的代谢和抗肿瘤活性之间的关系肿瘤。我们预计这个项目将产生新的机械洞察力，这可能导致免疫疗法的增强和个性化及其与化学疗法的结合，在各种癌症中获得更耐用的患者反应。呢