Graduation Date

Summer 8-9-2024

Document Type


Degree Name

Doctor of Philosophy (PhD)


Cancer Research

First Advisor

Joyce Solheim

MeSH Headings

Pancreatic Neoplasms, Immunomodulation, Drug Therapy


Pancreatic cancer is a lethal malignancy, with a five-year overall survival rate of just 13%. Current treatment approaches thus require modification and attention has shifted towards improving immunotherapy efficacy. Select chemotherapy drugs possess inherent immunomodulatory activity and could be used to initiate immunotherapeutic success, thereby restoring anti-tumor immunity in pancreatic cancer. In this work, I evaluated the impact of the chemotherapy drug gemcitabine on tumor antigen presentation by human leukocyte antigen class I (HLA-I). Gemcitabine regulated HLA-I expression on multiple levels, increasing pancreatic cancer cells’ HLA-I mRNA transcripts, total protein and surface expression, as well as surface stability. Temperature-dependent assay results suggested that the increased HLA-I stability may be due to reduced binding of low affinity peptides, and this was confirmed through immunopeptidome analysis via mass spectrometry. Computational prediction programs indicated that in addition to improved affinity, gemcitabine-exclusive peptides were also more immunogenic. Most of the gemcitabine-exclusive peptides originated from unique source proteins, and there was a notable overrepresentation of translation-related source proteins. Gemcitabine also induced expression of select immunoproteasome subunits, providing a potential explanation for its modulation of the HLA-I-presented peptidome. Moreover, regulation of HLA-I by gemcitabine seemed to be in part mediated by this drug's nucleotide-disrupting activities. My work supports continued investigation of immunotherapies to be used in combination with gemcitabine as a new treatment modality for pancreatic cancer.


2024 Copyright, the authors

Available for download on Friday, July 03, 2026