Abstract

Cancer associated cell-free DNA (cfDNA) and peripheral blood monocular cells (PBMCs) are circulating biomarkers capable of predicting risk of cancer recurrence and treatment associated adverse events, respectively. For my thesis research, I helped develop cfDNA and cellular minimally invasive liquid biopsies to predict both risk and toxicity. With respect to our cfDNA assays, we noticed plasma assays for locally advanced resectable solid tumors appeared to have lower sensitivity to detect locoregional minimal residual disease (MRD) early after surgery, when adjuvant treatment decision-making occurs. To enhance postoperative locoregional MRD detection in two malignancies of the aerodigestive tract, head and neck squamous cell carcinoma (HNSCC) and lung cancer, we developed cfDNA liquid biopsies using proximal postoperative biofluids collected from HNSCC and lung cancer patients following primary tumor resection and locoregional lymphadenectomy. In human papilloma virus-positive (HPV+) and negative (HPV-) HNSCC patients, the liquid biopsy utilized lymph fluid evacuating the neck dissection wound bed into Jackson Pratt surgical drains, and in lung cancer patients we used pleural fluid captured in chest tubes draining the thoracic cavity wound bed. We further quantified circulating tumor DNA (ctDNA) burden in the HNSCC postoperative lymph fluid by targeting cell-free HPV (cf-HPV) and tumor-informed variants, while in the lung cancer postoperative pleural fluid we assessed cancer-associated methylation signatures (ongoing), cancer-associated cfDNA fragmentation patterns (ongoing), and tumor-informed variants. Across resectable disease cancer patients in our cohorts, ctDNA signal in the proximal liquid analytes (lymph and pleural fluid) was enriched compared to matched postoperative plasma, correlated with nodal disease burden and high-risk pathologic features, and appeared to reflect both general recurrence risk and locoregional recurrences risk. Apart from this work, our group participated in a tri-institutional effort (with Yale Cancer Center and Stanford) to use pretreatment PBMCs collected from metastatic melanoma patients to discover cellular features of immune-checkpoint inhibitor (ICI)-associated immune toxicity. We defined two such toxicity-associated pretreatment characteristics on T cells in Lozano et. Al 2022; high abundance of CD4 T effector memory T cells and high global T cell receptor diversity (TCR). I helped conduct mass cytometry (CyTOF) and bulk RNA sequencing studies to prospectively validate both T cell characteristics in independent cohorts. Combining both T cell characteristics into a composite model showed model score was strongly correlated with severe (grade 3-4) immune-related adverse events (irAEs) and predicted shorter freedom from severe irAE development, while having no association with treatment response.

Committee Chair

Aadel Chaudhuri

Committee Members

Gwendalyn Randolph; Jin Zhang; Jose Zevallos; Julie Schwarz

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Immunology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

3-12-2026

Language

English (en)

Download

Available for download on Saturday, March 11, 2028

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