Graduation Date

Summer 8-11-2023

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Whitney Goldner

Second Advisor

Robert Bennett

Third Advisor

Hamid Band

Fourth Advisor

Apar Ganti

Abstract

Thyroid cancer is the most common endocrine malignancy, estimated to be the second most common cancer in women by 2030. The frequency of differentiated thyroid cancer (DTC), the most common subtype of thyroid cancer, is higher in patients with autoimmune thyroid disease but the influence of the immune milieu on thyroid carcinogenesis remains unclear. To address this gap in knowledge, we performed clinical and translational experiments to identify immune biomarkers for the occurrence and prognosis of DTC. Multiparameter flow cytometry of peripheral blood from 32 adults found advanced thyroid cancer either at presentation or during the disease-course to be associated with circulating suppressor immune phenotypes characterized by less CD4+ T cells, gamma-delta T cells and NK T-like cells but more myeloid-derived suppressor cells (MDSCs); and altered memory T cells. Building on these results, our investigation of the tumor immune microenvironment in 17 paired samples of DTC via multiplex immunofluorescence revealed more immune checkpoint programmed death ligand 1 (PD-L1) and a trend for more CD163 (M2 macrophage marker) intratumorally compared to adjacent thyroid tissue. Exploratory analysis found a trend for more PD-L1, CD68 (macrophage marker), and FOXP3 (T regulatory cell marker) in distant metastatic DTC cases suggesting their potential role as prognostic biomarkers. The key findings of immune alteration in circulation and tumor microenvironment of DTC served as the basis for our investigation of proteins relaxin (RLN2), which plays a role in M2 macrophage polarization and extracellular matrix remodeling, and EPS15 homology domain 1 (EHD1), which plays role in T-cell signaling. We identified these in surgical thyroid tissue from 181 adults with non-metastatic DTC compared to thyroid tissue from 185 adults with benign thyroid disease. The expression of these proteins, along with CD68 (macrophage marker) and CD163 (M2 macrophage marker), was significantly higher in cancerous compared to benign thyroid tissue, demonstrating their role as biomarkers in the occurrence and potentially prognosis of DTC. To conclude, the findings in this thesis demonstrate the role of the immune milieu in thyroid carcinogenesis. These findings are expected to be a significant contribution to the field of carcinogenesis by improving prognostication and identifying targets for novel therapies, thus heralding a new era in personalized patient care.

Comments

2023 Copyright, the authors

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Available for download on Friday, August 01, 2025

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