Date of Graduation

5-2017

Document Type

Thesis (MS)

Program Affiliation

Immunology

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Gheath Al-Atrash

Committee Member

Jeffrey Molldrem

Committee Member

Dean Lee

Committee Member

Joya Chandra

Committee Member

Greg Lizee

Abstract

Discovery of tumor-associated antigens is an important step in designing effective antigen-targeting immunotherapies. PR1 is a nonameric human leukocyte antigen (HLA)-A2 restricted leukemia-associated antigen derived from serine proteases neutrophil elastase (NE) and proteinase 3 (P3). NE and P3 are primarily expressed in cells of myeloid lineage including granulocytes, bone marrow progenitors and myeloid leukemia. Our lab reported that NE and P3 are cross-presented by antigen presenting cells (APCs) and solid tumors, a mechanism whereby exogenous antigens are endocytosed and presented on HLA class I molecules, inducing a cytotoxic T lymphocyte (CTL)-mediated immune response. Therefore, identifying non-myeloid tumors capable of PR1 cross-presentation broadens the application of PR1-targeted immunotherapies, which to date include PR1 peptide vaccine1, PR1 cellular therapy2,3 and 8F4, a T cell receptor (TCR)-like monoclonal antibody (mAb)4,5.

One possible source of NE and P3 in the microenvironment is neutrophil extracellular traps (NETs). NETs are composed of deoxyribonucleic acid (DNA)/histones extruded from polymorphonuclear neutrophils (PMNs) abundant in antimicrobial proteases, including NE and P3. Although a main function of NETs is elimination of pathogens, seminal studies have demonstrated immune-regulatory effects of NETs. Thus there lies a great interest in understanding the role of NETs in modulating adaptive immune system through cross-priming or cross-tolerance in the setting of anti-tumor immunity. We are specifically interested in possible roles of NETs in facilitating NE and P3 cross-presentation by acute lymphoblastic leukemia (ALL) due to its high abundance in the bone marrow.

The major aim of this study was to validate PR1 as a target in B-ALL. This hypothesis is based on strong data from our laboratory showing (1) uptake and cross-presentation of NE and P3 by APCs6,7 including B cells, and (2) susceptibility of non-myeloid tumors to killing by 8F4 and PR1-CTLs (PR1-specific cytotoxic T lymphocytes) following PR1 cross-presentation6. Knowledge gained will define PR1 as a therapeutic target and cross-presentation as a mechanism for antigen expression in B-ALL.

My results identify PR1 as a target in B cell-ALL, and identify NETs as a source of NE and P3 in the tumor microenvironment. These findings implicate the use of PR1-targeting immunotherapies as a novel form of treatment in B cell-ALL.

Keywords

cross-presentation, neutrophil elastase, proteinase 3, 8F4, PR1, acute lymphoblastic leukemia

Available for download on Saturday, May 05, 2018

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