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.
","abstract_html":"<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 vaccine<sup>1</sup>, PR1 cellular therapy<sup>2,3</sup> and 8F4, a T cell receptor (TCR)-like monoclonal antibody (mAb)<sup>4,5</sup>.</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<sup>6,7</sup> 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-presentation<sup>6</sup>. 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>","abstract_has_math":false,"creators":["Carmona, Selena"],"institution":null,"degree_name":"Masters of Science (MS)","degree_level":"Thesis (MS)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Gheath Al-Atrash","Jeffrey Molldrem","Dean Lee"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2017,"date_issued":"2017-05-01T07:00:00Z","date_published":"2017-05-01T07:00:00Z","updated_at":"2026-07-24T05:49:23Z","subjects":["cross-presentation","neutrophil elastase","proteinase 3","8F4","PR1","acute lymphoblastic leukemia","Medicine and Health Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/751","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Gheath Al-Atrash","Jeffrey Molldrem","Dean Lee"]},{"key":"dc:creator","label":"Author","values":["Carmona, Selena"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2019-05-05T07:00:00Z"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Thesis (MS)"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Masters of Science (MS)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["cross-presentation","neutrophil elastase","proteinase 3","8F4","PR1","acute lymphoblastic leukemia","Medicine and Health Sciences"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/751"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.
"]},{"key":"dc:title","label":"Title","values":["Characterizing The Source of Neutrophil Elastase and Proteinase 3 Cross-Presentation In B-Cell Acute Lymphoblastic Leukemia"]}]}],"canonical_facts":{"dc:contributor":["Gheath Al-Atrash","Jeffrey Molldrem","Dean Lee"],"dc:creator":["Carmona, Selena"],"dc:date.available":["2019-05-05T07:00:00Z"],"dc:description.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.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/751"],"dc:subject":["cross-presentation","neutrophil elastase","proteinase 3","8F4","PR1","acute lymphoblastic leukemia","Medicine and Health Sciences"],"dc:title":["Characterizing The Source of Neutrophil Elastase and Proteinase 3 Cross-Presentation In B-Cell Acute Lymphoblastic Leukemia"],"thesis:degree_level":["Thesis (MS)"],"thesis:degree_name":["Masters of Science (MS)"]},"updated_at":"2026-07-24T05:49:23Z"}