Dissertation
Novel prognostic biomarkers for oral squamous cell carcinoma
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2023
DOI: 10.25820/etd.006958
Abstract
Oral squamous cell carcinoma (OSCC) is the most common malignancy in the head and neck region. Despite advanced treatments such as targeted therapies and immune checkpoint therapy, the five-year survival rate is slightly more than 50% after diagnosis. Patients' clinicopathological characteristics, including tumor size, lymph node metastasis, and distant metastasis (TNM stage), as well as tumor differentiation, perineural invasion, lymphovascular invasion, and bone invasion, are generally used as indicators to predict patient outcomes. However, these indicators may not accurately predict patient prognosis, and not all high-risk patients can be identified using them.
Several attempts have been made to identify biomarkers for OSCC, and many potential markers have been proposed in the literature. However, none of them have been approved for clinical practice. Among these markers, Epidermal Growth Factor Receptor (EGFR) and Programmed Death-Ligand 1 (PD-L1) are of interest for our study since EGFR inhibitor (cetuximab, a targeted therapy) and programmed cell death protein (PD1) inhibitors (nivolumab and pembrolizumab, immune checkpoint inhibitors) have been approved by the Food and Drug Administration (FDA) for locally advanced and recurrent/metastatic head and neck cancer.
EGFR, which is involved in multiple pathways facilitating cancer growth, is a well-known prognostic biomarker for head and neck squamous cell carcinoma. PD-L1 is an immune checkpoint ligand. In the context of cancer, PD-L1 suppresses T-cell activity. The prognostic role of both EGFR and PD-L1 in OSCC is still controversial, with inconsistent findings reported in previous studies.
Other potential markers of interest in our study are tumor-infiltrating lymphocytes (TILs). TILs consist of multiple cell types, with the most common being T-cells composed of several subtypes with different functions. Cytotoxic CD8+ T-cells have been found to have a positive prognostic role in OSCC. CD4+ T-cells include helper T-cells and regulatory T-cells, and FOXP3 is a surrogate marker for regulatory T-cells. The prognostic value of CD4+ T-cells and FOXP3+ T-cells is still controversial.
Our objective in this study is to determine the optimal approach for evaluating the aforementioned indicators, with the goal of identifying patients who may experience poor survival outcomes. We constructed tissue microarrays using tissue specimens from the University of Iowa Hospital and Clinics, evaluated the expression of EGFR, PD-L1, and T-cell markers by immunohistochemistry, and correlated them with patients' clinicopathological characteristics and survival.
We found that high CD3 expression and CD8 expression were associated with better survival in EGFR+ OSCC patients. Low CD4 and CD8 expression can identify patients who have a worse outcome in early-stage OSCC. Furthermore, high PD-L1 expression evaluated using the 22C3 PharmDx antibody and combined positive score criteria, as well as high PD-L1 expression exclusively or mostly in cancer cells, can predict worse prognosis patients in those who receive surgery without history of radiation or chemoradiation.
Overall, we propose that the levels CD3+ T-cells and CD8+ T-cells may be helpful in interpreting the prognostic significance of EGFR. CD4+ T-cells and CD8+ T-cells might be helpful in predicting early-stage OSCC patients who will have cancer progression. Thirdly, PD-L1 can serve as a predictor of patients' survival when evaluated with FDA approved antibodies and criteria as well as based on the location of the expression in patients who received surgery as a single therapy. To confirm the prognostic significance of these markers and to enable their use in clinical practice, further investigation is warranted.
Details
- Title: Subtitle
- Novel prognostic biomarkers for oral squamous cell carcinoma
- Creators
- Wattawan Wongpattaraworakul
- Contributors
- Andrean Simons-Burnett (Advisor)Anand Rajan KD (Committee Member)John Hellstein (Committee Member)Marisa Buchakjian (Committee Member)Douglas Laux (Committee Member)Veeratrishul Allareddy (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Oral Science
- Date degree season
- Summer 2023
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.006958
- Number of pages
- xiv, 234 pages
- Copyright
- Copyright 2023 Wattawan Wongpattaraworakul
- Language
- English
- Date submitted
- 07/24/2023
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 218-234).
- Public Abstract (ETD)
- Oral squamous cell carcinoma (OSCC) is the most common type of head and neck cancer and a deadly disease. Despite advanced treatments, only slightly more than 50% of patients survive five years after diagnosis. While indicators like tumor size, cancer cells spreading to lymph nodes, cancer cells spreading to other organs (TNM stage), as well as invasion of the tumor into nerves, blood vessels, and bone are generally used to predict patient outcome, they are not always accurate in identifying high-risk patients who may eventually experience cancer progression or die from the disease.
Several potential biomarkers to predict worse prognosis of OSCC patients have been identified in previous literature; however, none of them have been approved for clinical use. Although drug targets Epidermal Growth Factor Receptor (EGFR) and Programmed Death-Ligand 1 (PD-L1) have been approved for use in head and neck cancer patients, the prognostic role of both of them is still unclear. Hence, we investigated the prognostic role of EGFR, a protein that is involved in cancer growth, and PD-L1, a ligand that is involved in the destruction of immune cells. Additionally, we also investigated specific types of tumor-infiltrating lymphocytes (CD3+, CD4+, CD8+, and FOXP3+ T-cells) that reflect the patient's immunity or resistance to cancer.
Overall, we propose that the levels CD3+ T-cells and CD8+ T-cells may be helpful in interpreting the prognostic significance of EGFR. CD4+ T-cells and CD8+ T-cells might be helpful in predicting early-stage OSCC patients who will have cancer progression. Thirdly, PD-L1 can serve as a predictor of patients' survival when evaluated with FDA-approved antibodies and criteria as well as based on the location of the expression in patients who received surgery as a single therapy. To confirm the prognostic significance of these markers and to enable their use in clinical practice, further investigation is warranted.
- Academic Unit
- Oral Pathology, Radiology and Medicine
- Record Identifier
- 9984454741802771
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