Investigating regulatory mechanisms of T cell effector function
Abstract/Contents
- Abstract
- T cells play an important role in recognizing and eliminating malignant cells, as well as providing protection from infectious pathogens. Multiple therapeutic modalities including vaccination, immune checkpoint blockade, and adoptive T cell therapy depend on robust T cell responses. Tumor microenvironments are often characterized by local immunosuppression and decreased T cell effector function. Consequently, increasing T cell effector activity in tumors is a common objective for the development of cancer therapeutics. Conversely, autoimmune disease progression is mediated by an imbalanced effector and regulatory immune response, prompting development of therapeutics to diminish T cell effector activity. Therefore, regulatory mechanisms that control differentiation and function of T cells are relevant for applications in medicine. In this dissertation, I will describe our work to identify regulators of T cell effector function. This question is first addressed in the context of cancer using a model system that mimics chronic antigen exposure to induce T cell dysfunction. Using genome-wide CRISPR screening, we identify the Meditator kinase module as a novel regulator of T cell function. We demonstrate this finding can be leveraged through genetic engineering and pharmacological approaches to augment T cell anti-tumor activity. This study further implicates interactions between the kinase module and core Mediator as a major axis of regulation of T cell differentiation. Technologies to inactivate genes are increasingly available for emerging applications in human medicine highlighting the potential for clinical translation of these findings. In the final chapter of this dissertation, I investigate the expression of immunomodulatory receptors in T cells isolated from patients with autoimmune disease. We identify receptors that are differentially expressed between effector and regulatory T cell subsets, providing a basis for selectively targeting effector T cells while preserving the function of regulatory T cells. Collectively, these studies explore multiple mechanisms to enhance or diminish T cell effector responses, providing new avenues for development of T cell directed therapeutics.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Freitas, Katherine Ann |
|---|---|
| Degree supervisor | Mackall, Crystal |
| Thesis advisor | Mackall, Crystal |
| Thesis advisor | Engleman, Edgar G |
| Thesis advisor | Majzner, Robbie |
| Thesis advisor | Satpathy, Ansuman |
| Degree committee member | Engleman, Edgar G |
| Degree committee member | Majzner, Robbie |
| Degree committee member | Satpathy, Ansuman |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Program in Immunology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Katherine Ann Freitas. |
|---|---|
| Note | Submitted to the Program in Immunology. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/kp456hd8349 |
Access conditions
- Copyright
- © 2023 by Katherine Ann Freitas
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