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Characterization of a new type of neoantigens in T-cell acute lymphoblastic leukemia (T-ALL) by cell surface terminomics Jenane, Lina
Abstract
Chemotherapy is the primary treatment for pediatric T cell acute lymphoblastic leukemia (T-ALL). While 80% of patients achieve long-term survival, the treatment's harsh nature can lead to acute and long-term side effects, posing significant psychosocial and economic burden for patients and their families. Therefore, there is an urgent need for more specific therapeutic targets for pediatric T-ALL. Protein mutations exposed on the cell surface are ideal therapeutic targets. However, previous studies have demonstrated that pediatric cancers have a lower mutational burden compared to adult cancers, resulting, in principle, in fewer targetable neoantigens, and presenting a major challenge for developing therapeutics. Proteolytic proteoforms present a new type of neoantigen with the potential to inform the development of highly selective pediatric treatments. In cancer, the microenvironment moulds a unique protective niche promoting carcinogenesis. This “safe heaven” has been partially characterized by dysregulated protease activity and associated cancer-specific proteolytic cleavages of cell surface proteins. As such, I hypothesized that T-ALL's unique microenvironment will generate cancer-specific proteolytic proteoforms on the cell surface of T-ALL cells. Identifying these alternate proteoforms can expand the list of potential therapeutic targets for pediatric T-ALL. Current global mass spectrometric workflows lack in coverage of cell surface N-termini. To meet this need, we developed a 1) biotin-based enrichment strategy for cell surface N termini; 2) mass spectrometric workflow; and 3) data analysis pipeline that allowed for the comprehensive assessment of the cell surface N terminome. I then applied this workflow to interrogate the cell surface terminomic changes (1) in Jurkat cells grown in acidic microenvironment and (2) in patient derived xenograft (PDX) expanded T-ALL cells in different organs and throughout disease progression. The strategy we developed was effective with a limited starting material (5 million cells). In, the PDX dataset, I identified HLA-B, CD2, ITAL4, CD99, TACT and PECA1 as candidates for further validation by flow and/or western blots. Ultimately, the identification of these cell surface termini, unique to T-ALL cells, offers potential targets for further validation for highly selective pediatric leukaemia treatments, presenting a promising therapeutic avenue.
Item Metadata
Title |
Characterization of a new type of neoantigens in T-cell acute lymphoblastic leukemia (T-ALL) by cell surface terminomics
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Creator | |
Supervisor | |
Publisher |
University of British Columbia
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Date Issued |
2024
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Description |
Chemotherapy is the primary treatment for pediatric T cell acute lymphoblastic leukemia (T-ALL). While 80% of patients achieve long-term survival, the treatment's harsh nature can lead to acute and long-term side effects, posing significant psychosocial and economic burden for patients and their families. Therefore, there is an urgent need for more specific therapeutic targets for pediatric T-ALL.
Protein mutations exposed on the cell surface are ideal therapeutic targets. However, previous studies have demonstrated that pediatric cancers have a lower mutational burden compared to adult cancers, resulting, in principle, in fewer targetable neoantigens, and presenting a major challenge for developing therapeutics.
Proteolytic proteoforms present a new type of neoantigen with the potential to inform the development of highly selective pediatric treatments. In cancer, the microenvironment moulds a unique protective niche promoting carcinogenesis. This “safe heaven” has been partially characterized by dysregulated protease activity and associated cancer-specific proteolytic cleavages of cell surface proteins. As such, I hypothesized that T-ALL's unique microenvironment will generate cancer-specific proteolytic proteoforms on the cell surface of T-ALL cells. Identifying these alternate proteoforms can expand the list of potential therapeutic targets for pediatric T-ALL.
Current global mass spectrometric workflows lack in coverage of cell surface N-termini. To meet this need, we developed a 1) biotin-based enrichment strategy for cell surface N termini; 2) mass spectrometric workflow; and 3) data analysis pipeline that allowed for the comprehensive assessment of the cell surface N terminome. I then applied this workflow to interrogate the cell surface terminomic changes (1) in Jurkat cells grown in acidic microenvironment and (2) in patient derived xenograft (PDX) expanded T-ALL cells in different organs and throughout disease progression.
The strategy we developed was effective with a limited starting material (5 million cells). In, the PDX dataset, I identified HLA-B, CD2, ITAL4, CD99, TACT and PECA1 as candidates for further validation by flow and/or western blots. Ultimately, the identification of these cell surface termini, unique to T-ALL cells, offers potential targets for further validation for highly selective pediatric leukaemia treatments, presenting a promising therapeutic avenue.
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Genre | |
Type | |
Language |
eng
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Date Available |
2024-06-20
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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DOI |
10.14288/1.0444001
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2024-11
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Campus | |
Scholarly Level |
Graduate
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Rights URI | |
Aggregated Source Repository |
DSpace
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International