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具有巨大的治疗前景，但目前 只有少数接受治疗的病人表现出持久的反应。免疫系统和免疫系统之间的相互作用 细胞和肿瘤细胞之间的相互作用是免疫疗法功效的关键决定因素。两种细胞 人口是高消费者的能量，并了解代谢过程中， 肿瘤微环境中的癌细胞和免疫细胞被认为是增加 免疫疗法的临床成功 该提案描述了一种新的技术方法来检查免疫代谢组学， 肿瘤内的细胞我们使用可植入的微型装置， 免疫细胞并局部探测它们对许多不同治疗和生物 药物，包括检查点抑制剂、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 使用质谱组织成像对400多种代谢物的群体进行分析， 每种代谢物与细胞增殖和抗肿瘤活性之间的定量关系 免疫细胞--都在天然肿瘤微环境中。 此外，该平台将用于直接跟踪代谢之间的竞争 免疫和肿瘤细胞，葡萄糖和谷氨酰胺在肝肿瘤通过同位素标记。 进行直接的、高通量的原位假设检验，以系统地解决 大量的免疫、细胞毒性和代谢调节剂重新编程 肿瘤中的各种细胞类型，以有利于免疫细胞的抗肿瘤活性。 直接在天然肿瘤微环境中混合化学和生物扰动， 由微型装置以高通量方式进行， 成像，以获得全面的代谢组学快照，代表了一种新的范例， 识别代谢和免疫细胞的抗肿瘤活性之间的关系， 肿瘤的我们预计这个项目将产生新的机械见解，可能导致 免疫疗法的增强和个性化，以及其与化疗的组合， 在各种癌症中获得更持久的患者反应。 !

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. !