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. !
This project seeks to provide a new approach for examining the metabolic activity of immune cells in tumors. Using implantable microdevices to deliver immunotherapies and other molecular probes that are capable of attracting and modulating immune cell activity in confined regions of the tumor in a multi-plexed manner, we employ Maldi mass spectrometry tissue imaging to generate in situ metabolic profiles of immune cells within the native tumor microenvironment. This approach will yield novel insight into competition between tumor and immune cells, how microenvironmental factors affect immune cell activity in tumors, and will inform potential therapeutic strategies to enhance the anti-tumor activity of immune cells.
