Author ORCID Identifier
https://orcid.org/0000-0002-6768-7690
Date of Graduation
5-2020
Document Type
Dissertation (PhD)
Program Affiliation
Immunology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Greg Lizee, PhD
Committee Member
Chantale Bernatchez, Ph.D.
Committee Member
Amir Jazaeri, M.D.
Committee Member
Dorothy Lewis, Ph.D.
Committee Member
Gheath Al-Atrash, D.O., Ph.D.
Abstract
Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regression by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from tumors of PDAC patients. This led to the identification of a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1), a novel putative TAA demonstrating overexpression in multiple tumor types and low or absent transcript expression in normal tissues with the exception of placenta. VGLL1-specific CTL isolated and expanded from the blood of a male PDAC patient showed the capacity to recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also ovarian, bladder, gastric, lung and basal-like breast cancers. Gene expression profiling revealed that VGLL1 is a member of a unique group of cancer-placenta antigens (CPA) that may constitute safe immunotherapeutic TAA targets for patients with multiple different cancer types. Additionally, we demonstrate that VGLL1 is associated with poorer patient survival rates in pancreatic cancer. However, its role in cancer remains largely uncharacterized. VGLL1 shares a similar binding motif to the TEAD family of genes with the oncogenes, YAP/TAZ that promote malignancies through the Hippo signaling pathway. We show that VGLL1 may play a significant role in tumorigenesis by inducing tumor cell proliferation, migration, and invasion.
Keywords
Immunology, T cell, Pancreatic Cancer, Immunotherapy, Immune cells, Immune system, Cancer, Therapy