| dc.description.abstract | Tissues and biological microenvironments, such as tumors, are structured and composed of multiple cell types. Each cell type can further be associated with a variety of cellular states, determined by gene expression profiling, which collectively perform functions. Studying the individual cells in the tissue can give insight into these functions, such as how a tissue develops or is perturbed during disease, and potentially how to intervene. High-throughput sequencing of the mRNA of single cells offers an unprecedented, high-resolution and comprehensive view of the biological activity of tissues and cell populations.
Here, I applied this technology to address two biological questions: (1) how T cell diversity changes over time in a tumor model of immune suppression, and (2) how the choroid plexus is specialized within --- and across --- ventricles and age.
The recent success of immunotherapy is a very promising avenue for cancer therapy. However, the responses of patients to immunotherapy are diverse and we do not currently have good biomarkers to predict treatment efficacy. This emphasizes the need for a deeper understating of mechanisms that limit immunotherapy efficacy, such as immune suppression. Here, I characterized the cellular states of tumor-infiltrating T cells and their modulations as the immune response becomes dysfunctional in a genetic mouse model of lung adenocarcinoma. T cells take on a diverse array of cellular states, depending strongly on their environment. By analyzing single-cell RNA-sequencing (scRNA-seq) data of T cells from an autochthonous murine tumor model, which develops over several months from endogenous tissue, I identified the IL-33 receptor ST2 as a potential regulator of an effector-like phenotype in regulatory T (Treg) cells. Indeed, Treg-specific deletion of Il1rl1 (encoding ST2) transformed the transcriptional landscape, increased CD8+ T cell infiltration, and decreased tumor burden. My analysis also revealed diverse cellular states of dysfunctional CD8+ T cells, which develop as the tumor progresses and exhibit distinct functional behavior.
Historically, the choroid plexus (ChP) was mainly considered a supportive tissue of the brain, yet recently there is rising interest in its roles as a regulator of brain development and function, as well as a point of entry for immune cells to the brain. To better understand the composition of this tissue and cellular heterogeneity within and across brain ventricles, I built an atlas of the murine choroid plexuses along developmental stages. Using scRNA-seq, our systematic approach identified that each ChP is composed of epithelial, endothelial, mesenchymal, immune, neuronal, and glial cells with distinct anatomical locations. Fibroblast populations, like epithelial, had regionalized transcriptional programs across brain ventricles that were maintained with age.
Overall, my work demonstrates the power of a comprehensive new method that allows us to study tissues at unprecedented resolution and generate a wealth of new hypotheses that are relevant for understanding how tissues develop and function. In summary, our work has brought new insight into cellular states in T cells that appear late during a chronic tumor response which might have therapeutic implications. Additionally, we built an atlas of the choroid plexus which will inform functional experiments to better understand the regulatory roles of the existing diversity in space and time. | |
