Defining the role of extracellular cGAMP signaling in health and disease
Abstract/Contents
- Abstract
- While cancer immunotherapy targeting the adaptive immune system has led to prolonged disease-free survival in otherwise terminal patients, there are few effective cancer therapies targeting the innate immune system. However, there is mounting evidence that the cGAMP-STING innate immune pathway is a promising anticancer target. While cGAMP is synthesized and functions inside the cytoplasm, recent evidence has shown that cGAMP is exported by cancer cells and imported by cGAMP-sensing responder cells in the host, thereby acting as a paracrine immunotransmitter. This thesis focuses on three key open questions in the field of extracellular cGAMP signaling: First, which cells within tumors directly respond to endogenous extracellular cGAMP? Second, how does cGAMP enter these cells? And third, can we specifically enhance extracellular cGAMP in vivo by inhibiting its degradation? We found that M1-polarized macrophages, monocytes, NK cells, and CD4+ T cells comprise the initial cGAMP-sensing populations within tumors. Additionally, we identified the first known cGAMP importer, SLC19A1, as well as the dominant cGAMP importer in primary human monocytes, SLC46A2. Finally, we discovered and characterized ENPP1-H362A, a point mutation that selectively inhibits cGAMP degradation while permitting normal ATP hydrolysis. While Enpp1-H362A mice do not exhibit the systemic calcification seen in Enpp1-null mice, they are significantly more resistant to HSV-1 infection and are more sensitive to radiation-induced inflammation, suggesting that extracellular cGAMP plays a critical role in broad disease contexts. Although we are still in the early stages of understanding this pathway, the extracellular cGAMP signaling pathway is a new frontier in immunotherapy that has the potential to revolutionize the treatment of a wide range of human diseases.
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 | Cordova, Anthony Frank |
|---|---|
| Degree supervisor | Li, Lingyin |
| Thesis advisor | Li, Lingyin |
| Thesis advisor | Dixon, Scott James, 1977- |
| Thesis advisor | Engleman, Edgar G |
| Thesis advisor | Long, Jonathan Z |
| Degree committee member | Dixon, Scott James, 1977- |
| Degree committee member | Engleman, Edgar G |
| Degree committee member | Long, Jonathan Z |
| Associated with | Stanford University, Cancer Biology Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Anthony Frank Cordova. |
|---|---|
| Note | Submitted to the Cancer Biology Program. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/ck812pk4618 |
Access conditions
- Copyright
- © 2021 by Anthony Frank Cordova
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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