Dissecting the Tumor Microennvironment in Oral Cancer Through Preclinical Modeling and Therapeutic Targeting

Gemalene M. Sunga (Advisor: Simon Young, DDS, MD, PhD; Secondary Advisor: Andrew Sikora, MD, PhD)

          In spite of promising advancements in the treatment of cancers, including head and neck and more specifically oral cancers, locally advanced solid tumors remain a major challenge. While immunotherapies have revolutionized cancer therapeutics, only 15-20% of patients with head and neck squamous cell carcinoma experience a durable response. It is critical, therefore, to advance preclinical models that effectively recapitulate the complexity of head and neck cancers and other such heterogenous diseases to ultimately develop effective therapeutic strategies. In this dissertation, the work described herein centers on the tumor immune microenvironment (TIME), which considers the interplay of tumor-immune cell interactions and largely influences tumor progression and treatment response. In our analysis of the immune landscape in heterotopic tumors of the novel ROC1 oral cancer model, we identify cells within the myeloid compartment, specifically myeloid-derived suppressor cells (MDSCs) and macrophages, as key suppressive populations in tumor progression. Next, we developed a translationally relevant orthotopic oral cancer resection model and detail the procedure for execution of this simplified and reproducible surgical model that is demonstrative of the standard-of-care treatment received by a majority of patients with oral cancer. This model was further utilized to study local and systemic immune dynamics following surgery and upon recurrence, revealing lymphoid cell expansion with checkpoint regulation as myeloid populations shift to a macrophage-driven wound-healing response. Finally, we translated insights from these studies into a potential therapeutic strategy to target dominant iNOS- and arginase-driven suppressive pathways in myeloid cell populations. This work so far has focused on establishing a critical experimental framework to evaluate this metabolic targeting of suppressive myeloid cells. Collectively, this work advances our understanding of the oral cancer TIME through the study and development of clinically relevant preclinical models, identification of immunosuppressive mechanisms, and evaluation of myeloid-targeted therapeutic strategies. Ultimately, this provides a foundation for the rational design of future immunotherapies.

Advisory Committee:

• Simon Young, DDS, MD, PhD, Chair
• Andrew Sikora, MD, PhD, Co-Chair
• Mary Farach-Carson, PhD
• Jeffrey Hartgerink, PhD
• Steven Lin, MD, PhD
• Linghua Wang, MD, PhD