Maurer, Deena M.
(2020)
Dysregulated NF-κB – dependent ICOSL Expression in Human Dendritic Cell Vaccines Impairs T Cell Responses in Melanoma Patients.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
FDA approved treatments for advanced melanoma have shown clinical efficiency in a subset of patients. Combinational therapy using checkpoint blockade has shown the most success, but many patients do not respond. The patients that do respond often have a pre-existing antitumor immunity. Dendritic cell (DC)-based vaccination can be used to help mount pre-existing immune responses. Although shown to be safe and immunogenic, the clinical response rate of DC vaccination remains low. We have profiled autologous DC vaccines used to treat 35 patients with advanced melanoma to identify potential biomarkers and signaling pathways that correlate with clinical outcomes. We show that DC expression of checkpoint molecules induced by ex vivo maturation of this therapeutic cell product correlates with in vivo vaccine activity. Importantly, melanoma patient DC were observed to express reduced levels of cell surface ICOSL and to be defective in intrinsic NF-kB signaling. ChIP assays revealed NF-kB-dependent transcriptional regulation of ICOSL expression. Blockade of ICOSL on DC reduced their capacity to prime antigen-specific CD8+ and CD4+ T cells in vitro. Additionally, levels of extracellular/soluble ICOSL released from vaccine DC positively correlated with clinical outcomes, which we have shown to be partially regulated by intrinsic ADAM10/17 sheddase activity. These data point to the critical role of canonical NF-kB signaling, the regulation of metalloproteinases, and DC-expressed/shed ICOSL in antigen-specific priming of T cell responses. In Appendix A, we used transcriptional profiling of patient and HD DC to identify disease-associated transcriptional differences. We observed that metabolic signaling pathways were dysregulated in patient mature DC (mDC). Functional assays showed that reduced activation of oxidative phosphorylation and fatty-acid β-oxidation in patient mDC correlated with immune responses and favorable outcomes. In Appendix B, another recent autologous DC vaccine (n=16) for the treatment of advanced melanoma is highlighted. We identified gene targets in patient DC that correlate with overall survival and immune response. These biomarkers are expected to serve as key biologic indices in defining therapeutic DC release criteria and endpoints for targeted interventional approaches designed to optimize the therapeutic anti-tumor efficacy of DC-based modalities or the intrinsic anti-tumor activities of DC in situ in cancer patients.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
21 December 2020 |
| Date Type: |
Publication |
| Defense Date: |
30 September 2020 |
| Approval Date: |
21 December 2020 |
| Submission Date: |
13 October 2020 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
140 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
ICOSL, cancer vaccine, NFκB Signaling , dendritic cells, melanoma |
| Additional Information: |
Co-mentored by Drs. Lisa H. Butterfield & Dr. Walter J. Storkus |
| Date Deposited: |
21 Dec 2020 15:49 |
| Last Modified: |
21 Dec 2020 15:49 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39783 |
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