Dissertation
Pharmacological modulation of Sigma1 as a means of regulating cancer cell adaptive immune resistance
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2020
DOI:
https://doi.org/10.17918/00001393
Abstract
Adaptive immune resistance in the context of cancer is a process by which cancer cells evade anti-tumor immunity by changing phenotype in response to proinflammatory immune signals, including cytokines such as interferon-gamma. One protein upregulated during this process is Programmed Death Ligand 1 (PD-L1). Cell surface PD-L1 acts as an inhibitory immune checkpoint molecule by binding PD-1 on activated T cells, resulting in suppression of the anti-tumor immune response. PD-L1 can also be incorporated onto cancer cell-derived extracellular vesicles (EVs), which can inactivate T cells both within the tumor microenvironment (TME) and at distant sites. EV cargo proteins have been shown to be important in immune modulation and TME remodeling in cancer. Sigma1 is a unique ligand-regulated integral membrane protein enriched in the endoplasmic reticulum (ER) of cancer cells. Sigma1 acts as a multi-functional scaffolding protein that regulates protein and lipid homeostasis in the secretory pathway of cells. This dissertation examines how Sigma1 can be pharmacologically targeted to suppress both PD-L1 and cancer cell EVs to promote anti-tumor immunity. We found that a selective small molecule Sigma1 inhibitor prevented interferon-gamma induced PD-L1 from progressing through the secretory pathway by blocking its maturation, thus suppressing cell-surface expression and T cell inactivation. The Sigma1 inhibitor also suppressed the production of EVs and the amount of PD-L1 packaged into EVs. By reducing cell surface and EV-associated PD-L1, Sigma1 inhibitors could provide a novel approach to enhancing anti-tumor immunity.
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Details
- Title
- Pharmacological modulation of Sigma1 as a means of regulating cancer cell adaptive immune resistance
- Creators
- Derick Allen Haas
- Contributors
- Felix J. Kim (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 108 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991014695537404721