Discovery and characterization of glyco-immune checkpoints
Abstract/Contents
- Abstract
- Glycans are complex polysaccharides that decorate the surface of every cell in the human body and have functions spanning many essential aspects of cell and organismal biology. Despite the importance of glycans to normal physiology and disease, relatively few drugs targeting mammalian glycans have been developed, in part due to the challenge of identifying glycans that are the causative agents of disease. In this thesis, I describe the discovery of glycans and glycan receptors that contribute to cancer and neurodegenerative disease by tuning immune cell function. Chapter 1 surveys drug development efforts in glycobiology through an historical lens and examines how identification of suitable targets is among the largest impediments to development of glycan-directed therapeutics. Chapter 2 details efforts to identify glycans that contribute to cancer growth. I find that MYC, one of the most commonly dysregulated human oncogenes, coordinates production of glycans that promote malignancy. I discover a specific glycan that facilitates tumor progression by enabling leukemia cells to engage immune cell Siglec receptors and avoid clearance by phagocytes. Chapter 3 expands on cancer glycosylation by identifying the glycolipid GD2 on neuroblastoma as an additional ligand for macrophage Siglecs. These data provide a molecular rationale for a novel immunotherapy comprising combined blockade of GD2 and CD47. Chapter 4 describes the use of CRISPR/Cas9 genetic screens to discover and characterize physiologically relevant glycan-receptor interactions. Microglia expressing the Siglec CD22 are found to have impaired phagocytic capacity which contributes to age-related cognitive decline. In sum, this dissertation identifies glycan targets in cancer and neurodegeneration, and presents a framework for further drug development efforts in glycobiology.
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 | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Smith, Benjamin |
|---|---|
| Degree supervisor | Bertozzi, Carolyn R, 1966- |
| Thesis advisor | Bertozzi, Carolyn R, 1966- |
| Thesis advisor | Chen, James Kenneth |
| Thesis advisor | Felsher, Dean (Dean Walton) |
| Thesis advisor | Wandless, Thomas |
| Degree committee member | Chen, James Kenneth |
| Degree committee member | Felsher, Dean (Dean Walton) |
| Degree committee member | Wandless, Thomas |
| Associated with | Stanford University, Department of Chemical and Systems Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Benjamin Arthur Humphers Smith. |
|---|---|
| Note | Submitted to the Department of Chemical and Systems Biology. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/mx717gj0608 |
Access conditions
- Copyright
- © 2021 by Benjamin Smith
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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