Characterizing The Source of Neutrophil Elastase and Proteinase 3 Cross-Presentation In B-Cell Acute Lymphoblastic Leukemia

<p>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 therapy^2,3 and 8F4, a T cell receptor (TCR)-like monoclonal antibody (mAb)^4,5.</p> <p>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.</p> <p>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 APCs^6,7 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.</p> <p>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.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2017

Author dc:creator

• Carmona, Selena

Contributors dc:contributor

• Gheath Al-Atrash
• Jeffrey Molldrem
• Dean Lee

• cross-presentation
• neutrophil elastase
• proteinase 3
• 8F4
• PR1
• acute lymphoblastic leukemia
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/751

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1811