Eliciting anti-tumor immunity via targeted immunostimulant therapy
Abstract/Contents
- Abstract
- Promoting immune activation within the tumor microenvironment (TME) is a promising therapeutic strategy to reverse tumor immunosuppression and elicit anti-tumor immunity. To enable tumor-localized immunotherapy following intravenous administration, we chemically conjugated a polyspecific integrin-binding peptide (PIP) to an immunostimulant (TLR9 agonist: CpG) to generate a tumor-targeted immunomodulatory agent, referred to as PIP-CpG. We demonstrate that systemic delivery of PIP-CpG induces tumor regression and enhances therapeutic efficacy compared to untargeted CpG in implanted murine breast and pancreatic cancer models. Furthermore, PIP-CpG therapy was able to inhibit tumor growth and prolong survival of MMTV-PyMT transgenic mice, which spontaneously develop multiple breast tumors. Mechanistically, PIP-CpG transforms the immunosuppressive TME into a lymphocyte-rich TME infiltrated with activated CD8+ T cells, CD4+ T cells, and B cells. This TME transformation was also observed upon treatment with intratumoral CpG but not systemic CpG, indicating that tumor-localized delivery is critical for remodeling the TME. Consistent with these findings, we show that tumor-specific effector CD8+ T cells are generated in response to PIP-CpG therapy and that T cells are required for therapeutic efficacy, demonstrating that efficient delivery of CpG to the tumor site elicits T cell-mediated anti-tumor immunity. Finally, we show that the efficacy of PIP-CpG can be enhanced using combination therapy with a T-cell-modulating anti-OX40 antibody. Overall, these results highlight the therapeutic potential of promoting immune activation in the TME and demonstrate that conjugating an immunostimulant to a tumor-targeting peptide is a viable strategy to achieve this goal.
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 | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Miller, Caitlyn Lee |
|---|---|
| Degree supervisor | Bertozzi, Carolyn R, 1966- |
| Degree supervisor | Cochran, Jennifer R |
| Thesis advisor | Bertozzi, Carolyn R, 1966- |
| Thesis advisor | Cochran, Jennifer R |
| Thesis advisor | Appel, Eric (Eric Andrew) |
| Thesis advisor | Levy, Ronald, 1941 December 6- |
| Degree committee member | Appel, Eric (Eric Andrew) |
| Degree committee member | Levy, Ronald, 1941 December 6- |
| Associated with | Stanford University, Department of Bioengineering |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Caitlyn L. Miller. |
|---|---|
| Note | Submitted to the Department of Bioengineering. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/dt604tz9504 |
Access conditions
- Copyright
- © 2022 by Caitlyn Lee Miller
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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