Leveraging a cancer drug's off-target effects
Abstract/Contents
- Abstract
- Red blood cells (erythrocytes, RBCs) are common to almost all vertebrate life on earth. In humans, RBCs circulate for approximately 120 days prior to their phago-cytic destruction by macrophages. RBCs are protected from premature destruction by their expression of the surface protein CD47, which interacts with the macrophage surface receptor SIRPa to inhibit phagocytosis. CD47 is expressed by all cells, and is overexpressed in many cancers. Antibody-mediated blockade of the CD47-SIRPa interaction overcomes this resistance, promoting macrophage-mediated destruction of cancer cells. This strategy works both by disrupting the anti-phagocytic CD47-SIRPa interaction and by engaging pro-phagocytic macrophage-expressed Fc gamma receptors (FcgRs). While a number of CD47-blocking antibodies are now in clinical trials for cancer immunotherapy, one question remains: how are patients able to tolerate CD47 antibody, given that it sensitizes their RBCs to phagocytic destruction? We find that CD47 antibody therapy induces myeloid FcgR-mediated pruning of RBC CD47 in mice, with global concomitant myeloid FcgR loss and splenic myeloid phagocytic inhibition, which protect antibody-bound and CD47-deficient RBCs from phagocytosis. Our findings provide a mechanism for the surprising tolerability of CD47 blocking antibodies and a mechanism by which RBC-binding antibodies may protect against autoimmune destruction of circulating cells like RBCs and platelets.
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 | Markovic, Maxim |
|---|---|
| Degree supervisor | Nolan, Garry P |
| Degree supervisor | Weissman, Irving L |
| Thesis advisor | Nolan, Garry P |
| Thesis advisor | Weissman, Irving L |
| Thesis advisor | Angelo, Michael, (Pathologist) |
| Thesis advisor | Jaiswal, Siddhartha |
| Degree committee member | Angelo, Michael, (Pathologist) |
| Degree committee member | Jaiswal, Siddhartha |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Cancer Biology Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Maxim Markovic. |
|---|---|
| Note | Submitted to the Cancer Biology Program. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/vp505cd7235 |
Access conditions
- Copyright
- © 2023 by Maxim Markovic
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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