The programmed cell death protein 1 (PD-1) pathway in cancer : engineering protein therapeutics and exploring a novel role for PD-1 on tumor-infiltrating macrophages
Abstract/Contents
- Abstract
- Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells to induce tolerance.1,2 Tumor cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), allowing escape from the immune system.3,4 Several monoclonal antibodies blocking PD-1/PD-L1 are clinically approved, and lead to remarkable efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small cell lung cancer, and Hodgkin's lymphoma.5-10 However, antibodies have inherent limitations that can curtail their efficacy in this setting, including poor tissue/tumor penetrance and detrimental Fc-effector functions that deplete immune cells. To determine if PD-1:PD-L1 directed immunotherapy could be improved with smaller, non-antibody therapeutics, I used directed-evolution by yeast-surface display to engineer the PD-1 ectodomain as a high-affinity (110 pM) competitive antagonist of PD-L1. In contrast to anti-PD-L1 monoclonal antibodies, high-affinity PD-1 demonstrated superior tumor penetration without inducing depletion of peripheral effector T cells. Consistent with these advantages, in syngeneic CT26 tumor models, high affinity PD-1 was effective in treating both small (50 mm3) and large tumors (150 mm3), whereas the activity of anti-PD-L1 antibodies was completely abrogated against large tumors. Furthermore, I found that high-affinity PD-1 could be radiolabeled and applied as a PET imaging tracer to efficiently distinguish between PD-L1-positive and PD-L1-negative tumors in living mice, providing an alternative to invasive biopsy and histological analysis. These results thus highlight the favorable pharmacology of small, non-antibody therapeutics for enhanced cancer immunotherapy and immune diagnostics. Although it is well-established that PD-1/PD-L1 blockade activates T cells, little is known about the role that this pathway may have on tumor-associated macrophages (TAMs). As such, I also investigate a functional role for PD-1 on TAMs. I show that both mouse and human TAMs express PD-1. TAM PD-1 expression increases over time in mouse models, and with increasing disease stage in primary human cancers. TAM PD-1 expression negatively correlates with phagocytic potency against tumor cells, and blockade of PD-1/PD-L1 in vivo increases macrophage phagocytosis, reduces tumor growth, and lengthens survival in mouse models of cancer in a macrophage-dependent fashion. My results suggest that PD-1/PD-L1 therapies may also function through a direct effect on macrophages, with significant implications for treatment with these agents.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2017 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Gordon, Sydney |
|---|---|
| Associated with | Stanford University, Department of Molecular and Cellular Physiology. |
| Primary advisor | Weissman, Irving L |
| Thesis advisor | Weissman, Irving L |
| Thesis advisor | Beachy, Philip Arden |
| Thesis advisor | Feng, Liang, 1976- |
| Thesis advisor | Majeti, Ravindra, 1972- |
| Advisor | Beachy, Philip Arden |
| Advisor | Feng, Liang, 1976- |
| Advisor | Majeti, Ravindra, 1972- |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Sydney Gordon. |
|---|---|
| Note | Submitted to the Department of Molecular and Cellular Physiology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2017. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2017 by Sydney Rin Anna Gordon
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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