ORCID ID
Graduation Date
Spring 5-9-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Cancer Research
First Advisor
Michael A. Hollingsworth
Abstract
Pancreatic adenocarcinoma has a 13% 5-year survival rate and limited curative therapeutic options outside of surgical resection at an early stage. Recent studies have indicated that the few patients who live longer than 5 years with this disease have high-quality neoantigens: mutated cancer-specific proteins that are recognizable by the immune system. This has led to various approaches aimed at training the immune system to recognize these neoantigens in patients. Targeting neoantigens is a difficult endeavor, as neopeptides derived from neoantigens vary significantly between patients based on their own unique major histocompatibility complex (MHC) alleles and cancer mutations. This body of work aims to expand neoantigen discovery in pancreatic adenocarcinoma by examining personalized neoantigen strategies based on mutations identified in tumor DNA, while also characterizing the efficacy of shared (“off-the-shelf”) neoantigen targeting based on known, highly conserved, KRAS mutations. First, we performed whole exome sequencing and MHC-I peptide elution on pancreatic ductal adenocarcinoma (PDAC) liver metastases. Genome-based neoantigens predicted from the exome were compared against the 25,500 peptides eluted from MHC class I. We discovered no overlap between these two populations, indicating that MHC class I did not present targetable neopeptides predicted from exome data. Further analysis revealed that these mutated proteins were expressed an order of magnitude lower at the RNA level relative to the proteins whose peptides were presented on MHC class I. In parallel, we assessed 9 patients with pancreatic pathology (PDAC or cystic lesions) for the presence of immune cells reactive to KRAS G12V peptides. We discovered that 3/9 patients had underlying reactivity to G12V and 1/9 had underlying G12R reactivity. In silico analysis revealed that KRAS mutant peptide G12V was predicted to bind to more MHC class I alleles than any other KRAS mutation. Examination of the impact of mutant KRAS peptide-binding MHC alleles on overall survival in PDAC within The Cancer Genome Atlas (TCGA) revealed no correlation. Overall, while much of this work is still in its infancy, the findings of this thesis help define what obstacles need to be addressed and what future studies need to be conducted.
Rights
The author holds the copyright to this work and any reuse or permissions must be obtained from the author directly.
Recommended Citation
Miklavcic, William R., "Identifying Reliably Expressed Neoantigens Presented on Major Histocompatibility Complex Class I in Pancreatic Adenocarcinoma" (2026). Theses & Dissertations. 1039.
https://digitalcommons.unmc.edu/etd/1039