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Evaluation of tumor antigen-specific antibody responses in patients with metastatic triple negative breast cancer treated with cyclophosphamide and pembrolizumab

The role of B cells in antitumor immunity is becoming increasingly appreciated, as B cell populations have been associated with response to immune checkpoint blockade (ICB) in patients with breast cancer and murine models of breast cancer. Deeper understanding of antibody responses to tumor antigens...

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Autores principales: Routh, Eric D, Woodcock, Mark G, Beckabir, Wolfgang, Vensko, Steven P, Serody, Jonathan S, Vincent, Benjamin G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10008414/
https://www.ncbi.nlm.nih.gov/pubmed/36882226
http://dx.doi.org/10.1136/jitc-2022-005848
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author Routh, Eric D
Woodcock, Mark G
Beckabir, Wolfgang
Vensko, Steven P
Serody, Jonathan S
Vincent, Benjamin G
author_facet Routh, Eric D
Woodcock, Mark G
Beckabir, Wolfgang
Vensko, Steven P
Serody, Jonathan S
Vincent, Benjamin G
author_sort Routh, Eric D
collection PubMed
description The role of B cells in antitumor immunity is becoming increasingly appreciated, as B cell populations have been associated with response to immune checkpoint blockade (ICB) in patients with breast cancer and murine models of breast cancer. Deeper understanding of antibody responses to tumor antigens is needed to clarify the function of B cells in determining response to immunotherapy. We evaluated tumor antigen-specific antibody responses in patients with metastatic triple negative breast cancer treated with pembrolizumab following low-dose cyclophosphamide therapy using computational linear epitope prediction and custom peptide microarrays. We found that a minority of predicted linear epitopes were associated with antibody signal, and signal was associated with both neoepitopes and self-peptides. No association was observed between signal presence and subcellular localization or RNA expression of parent proteins. Patient-specific patterns of antibody signal boostability were observed that were independent of clinical response. Intriguingly, measures of cumulative antibody signal intensity relative to immunotherapy treatment showed that the one complete responder in the trial had the greatest increase in total antibody signal, which supports a potential association between ICB-dependent antibody boosting and clinical response. The antibody boost in the complete responder was largely driven by increased levels of IgG specific to a sequence of N-terminal residues in native Epidermal Growth Factor Receptor Pathway Substrate 8 (EPS8) protein, a known oncogene in several cancer types including breast cancer. Structural protein prediction showed that the targeted epitope of EPS8 was in a region of the protein with mixed linear/helical structure, and that this region was solvent-exposed and not predicted to bind to interacting macromolecules. This study highlights the potential importance of the humoral immune response targeting neoepitopes as well as self epitopes in shaping clinical response to immunotherapy.
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spelling pubmed-100084142023-03-13 Evaluation of tumor antigen-specific antibody responses in patients with metastatic triple negative breast cancer treated with cyclophosphamide and pembrolizumab Routh, Eric D Woodcock, Mark G Beckabir, Wolfgang Vensko, Steven P Serody, Jonathan S Vincent, Benjamin G J Immunother Cancer Immunotherapy Biomarkers The role of B cells in antitumor immunity is becoming increasingly appreciated, as B cell populations have been associated with response to immune checkpoint blockade (ICB) in patients with breast cancer and murine models of breast cancer. Deeper understanding of antibody responses to tumor antigens is needed to clarify the function of B cells in determining response to immunotherapy. We evaluated tumor antigen-specific antibody responses in patients with metastatic triple negative breast cancer treated with pembrolizumab following low-dose cyclophosphamide therapy using computational linear epitope prediction and custom peptide microarrays. We found that a minority of predicted linear epitopes were associated with antibody signal, and signal was associated with both neoepitopes and self-peptides. No association was observed between signal presence and subcellular localization or RNA expression of parent proteins. Patient-specific patterns of antibody signal boostability were observed that were independent of clinical response. Intriguingly, measures of cumulative antibody signal intensity relative to immunotherapy treatment showed that the one complete responder in the trial had the greatest increase in total antibody signal, which supports a potential association between ICB-dependent antibody boosting and clinical response. The antibody boost in the complete responder was largely driven by increased levels of IgG specific to a sequence of N-terminal residues in native Epidermal Growth Factor Receptor Pathway Substrate 8 (EPS8) protein, a known oncogene in several cancer types including breast cancer. Structural protein prediction showed that the targeted epitope of EPS8 was in a region of the protein with mixed linear/helical structure, and that this region was solvent-exposed and not predicted to bind to interacting macromolecules. This study highlights the potential importance of the humoral immune response targeting neoepitopes as well as self epitopes in shaping clinical response to immunotherapy. BMJ Publishing Group 2023-03-07 /pmc/articles/PMC10008414/ /pubmed/36882226 http://dx.doi.org/10.1136/jitc-2022-005848 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Immunotherapy Biomarkers
Routh, Eric D
Woodcock, Mark G
Beckabir, Wolfgang
Vensko, Steven P
Serody, Jonathan S
Vincent, Benjamin G
Evaluation of tumor antigen-specific antibody responses in patients with metastatic triple negative breast cancer treated with cyclophosphamide and pembrolizumab
title Evaluation of tumor antigen-specific antibody responses in patients with metastatic triple negative breast cancer treated with cyclophosphamide and pembrolizumab
title_full Evaluation of tumor antigen-specific antibody responses in patients with metastatic triple negative breast cancer treated with cyclophosphamide and pembrolizumab
title_fullStr Evaluation of tumor antigen-specific antibody responses in patients with metastatic triple negative breast cancer treated with cyclophosphamide and pembrolizumab
title_full_unstemmed Evaluation of tumor antigen-specific antibody responses in patients with metastatic triple negative breast cancer treated with cyclophosphamide and pembrolizumab
title_short Evaluation of tumor antigen-specific antibody responses in patients with metastatic triple negative breast cancer treated with cyclophosphamide and pembrolizumab
title_sort evaluation of tumor antigen-specific antibody responses in patients with metastatic triple negative breast cancer treated with cyclophosphamide and pembrolizumab
topic Immunotherapy Biomarkers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10008414/
https://www.ncbi.nlm.nih.gov/pubmed/36882226
http://dx.doi.org/10.1136/jitc-2022-005848
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