Dissertations and Theses (Open Access)

Author ORCID Identifier

https://orcid.org/0000-0001-9301-3780

Date of Graduation

8-2026

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Simon Young

Committee Member

Andrew G. Sikora

Committee Member

Jeffrey D. Hartgerink

Committee Member

Mary C. Farach-Carson

Committee Member

Zhiqiang An

Abstract

Most head and neck squamous cell carcinoma (HNSCC) patients do not respond to single-agent immunotherapy, largely due to the immunosuppressive tumor immune microenvironment (TIME). Therefore, understanding the TIME and tumor-draining lymph nodes is critical for improving immunotherapy responses. Current FDA-approved immunotherapies are administered systemically. Thus, examining circulating immune cells, as well as immune responses in peripheral tissues such as blood and spleen, may provide insights into generating durable systemic immunity. In this dissertation, the tumor immune microenvironment and peripheral immune responses were immune profiled in a clinically relevant HPV-negative orthotopic oral cancer model to identify mechanisms of immunosuppression. The insights from the TIME were leveraged to guide the design and localize delivery of immunotherapies. Then, I applied localized immunotherapy delivery strategies including multiple intratumoral injections of a stimulator of interferon genes (STING) agonist and a single-dose of the STING agonist loaded-dual-biomaterial system in combination with systemic delivery of immune checkpoint inhibitors in the HPV-negative orthotopic oral cancer model. In conclusion, the single-dose of the dual-biomaterial system was able to localize the delivery of the immunomodulator as effectively as the multiple intratumoral injections. Finally, intratumoral delivery of interleukin-12 (IL-12) and systemic anti-programmed cell death protein-1 (α-PD-1) therapies were administered across oral cancer models with varying immune-infiltration to inform context-specific immunotherapy design and application. In summary, understanding the dynamic composition of the TIME and host immune response during disease progression will guide the selection of combination therapies and effective delivery approaches.

Keywords

tumor immune microenvironment, head and neck cancer, immunotherapy, STING, IL-12, immune checkpoint blockade, biomaterials, local delivery, intratumoral

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Available for download on Saturday, August 07, 2027

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