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

摘要： 免疫疗法在许多癌症适应症中都有很大的治疗前景，但目前 只有一小部分接受治疗的患者表现出持久的反应。免疫之间的相互作用 细胞和肿瘤细胞是免疫治疗效果的关键决定因素。两个单元格 人群是能源的高消耗者，了解人类的代谢过程 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。 这项建议描述了一种新的技术方法来研究免疫代谢组学。 肿瘤内的细胞。我们使用可植入的微型设备，使我们能够有选择地吸引 免疫细胞和局部探测它们对许多不同的治疗和生物反应 药物，包括检查点抑制物、细胞因子和趋化因子、代谢调节剂 活性和抗癌剂。由此产生的富含免疫细胞的肿瘤内区域 使用质谱学组织成像对人群进行400+代谢物的分析，提供 各代谢物与细胞增殖及抗肿瘤活性的定量关系 免疫细胞--都在天然的肿瘤微环境中。 此外，该平台还将被用来直接跟踪 免疫和肿瘤细胞，通过同位素标记活体肿瘤中的葡萄糖和谷氨酰胺。 执行直接、高通量的现场假设检验，以系统地解决 一大套免疫、细胞毒性和代谢调节剂重新编程 肿瘤中多种细胞类型有利于免疫细胞的抗肿瘤活性。 直接在自然肿瘤微环境中的化学和生物扰动的混合， 由微器件以高通量方式与质谱学组织一起执行 成像以获得全面的代谢快照，代表了一种新的范式 辨别免疫细胞代谢与抗肿瘤活性的关系 肿瘤。我们预计这个项目将产生新的机械洞察力，可能导致 免疫治疗的增强和个性化，及其与化疗的结合，以 在各种癌症中获得更持久的患者反应。 好了！

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. !