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Dynamics of Melanoma-Associated Epitope-Specific CD8+ T Cells in the Blood Correlate With Clinical Outcome Under PD-1 Blockade
Immune checkpoint blockade (ICB) is standard-of-care for patients with metastatic melanoma. It may re-invigorate T cells recognizing tumors, and several tumor antigens have been identified as potential targets. However, little is known about the dynamics of tumor antigen-specific T cells in the circ...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9300827/ https://www.ncbi.nlm.nih.gov/pubmed/35874702 http://dx.doi.org/10.3389/fimmu.2022.906352 |
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author | Gaißler, Andrea Meldgaard, Trine Sundebo Heeke, Christina Babaei, Sepideh Tvingsholm, Siri Amanda Bochem, Jonas Spreuer, Janine Amaral, Teresa Wagner, Nikolaus Benjamin Klein, Reinhild Meier, Friedegund Garbe, Claus Eigentler, Thomas K. Pawelec, Graham Claassen, Manfred Weide, Benjamin Hadrup, Sine Reker Wistuba-Hamprecht, Kilian |
author_facet | Gaißler, Andrea Meldgaard, Trine Sundebo Heeke, Christina Babaei, Sepideh Tvingsholm, Siri Amanda Bochem, Jonas Spreuer, Janine Amaral, Teresa Wagner, Nikolaus Benjamin Klein, Reinhild Meier, Friedegund Garbe, Claus Eigentler, Thomas K. Pawelec, Graham Claassen, Manfred Weide, Benjamin Hadrup, Sine Reker Wistuba-Hamprecht, Kilian |
author_sort | Gaißler, Andrea |
collection | PubMed |
description | Immune checkpoint blockade (ICB) is standard-of-care for patients with metastatic melanoma. It may re-invigorate T cells recognizing tumors, and several tumor antigens have been identified as potential targets. However, little is known about the dynamics of tumor antigen-specific T cells in the circulation, which might provide valuable information on ICB responses in a minimally invasive manner. Here, we investigated individual signatures composed of up to 167 different melanoma-associated epitope (MAE)-specific CD8+ T cells in the blood of stage IV melanoma patients before and during anti-PD-1 treatment, using a peptide-loaded multimer-based high-throughput approach. Additionally, checkpoint receptor expression patterns on T cell subsets and frequencies of myeloid-derived suppressor cells and regulatory T cells were quantified by flow cytometry. Regression analysis using the MAE-specific CD8+ T cell populations was applied to identify those that correlated with overall survival (OS). The abundance of MAE-specific CD8+ T cell populations, as well as their dynamics under therapy, varied between patients. Those with a dominant increase of these T cell populations during PD-1 ICB had a longer OS and progression-free survival than those with decreasing or balanced signatures. Patients with a dominantly increased MAE-specific CD8+ T cell signature also exhibited an increase in TIM-3+ and LAG-3+ T cells. From these results, we created a model predicting improved/reduced OS by combining data on dynamics of the three most informative MAE-specific CD8+ T cell populations. Our results provide insights into the dynamics of circulating MAE-specific CD8+ T cell populations during ICB, and should contribute to a better understanding of biomarkers of response and anti-cancer mechanisms. |
format | Online Article Text |
id | pubmed-9300827 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93008272022-07-22 Dynamics of Melanoma-Associated Epitope-Specific CD8+ T Cells in the Blood Correlate With Clinical Outcome Under PD-1 Blockade Gaißler, Andrea Meldgaard, Trine Sundebo Heeke, Christina Babaei, Sepideh Tvingsholm, Siri Amanda Bochem, Jonas Spreuer, Janine Amaral, Teresa Wagner, Nikolaus Benjamin Klein, Reinhild Meier, Friedegund Garbe, Claus Eigentler, Thomas K. Pawelec, Graham Claassen, Manfred Weide, Benjamin Hadrup, Sine Reker Wistuba-Hamprecht, Kilian Front Immunol Immunology Immune checkpoint blockade (ICB) is standard-of-care for patients with metastatic melanoma. It may re-invigorate T cells recognizing tumors, and several tumor antigens have been identified as potential targets. However, little is known about the dynamics of tumor antigen-specific T cells in the circulation, which might provide valuable information on ICB responses in a minimally invasive manner. Here, we investigated individual signatures composed of up to 167 different melanoma-associated epitope (MAE)-specific CD8+ T cells in the blood of stage IV melanoma patients before and during anti-PD-1 treatment, using a peptide-loaded multimer-based high-throughput approach. Additionally, checkpoint receptor expression patterns on T cell subsets and frequencies of myeloid-derived suppressor cells and regulatory T cells were quantified by flow cytometry. Regression analysis using the MAE-specific CD8+ T cell populations was applied to identify those that correlated with overall survival (OS). The abundance of MAE-specific CD8+ T cell populations, as well as their dynamics under therapy, varied between patients. Those with a dominant increase of these T cell populations during PD-1 ICB had a longer OS and progression-free survival than those with decreasing or balanced signatures. Patients with a dominantly increased MAE-specific CD8+ T cell signature also exhibited an increase in TIM-3+ and LAG-3+ T cells. From these results, we created a model predicting improved/reduced OS by combining data on dynamics of the three most informative MAE-specific CD8+ T cell populations. Our results provide insights into the dynamics of circulating MAE-specific CD8+ T cell populations during ICB, and should contribute to a better understanding of biomarkers of response and anti-cancer mechanisms. Frontiers Media S.A. 2022-07-07 /pmc/articles/PMC9300827/ /pubmed/35874702 http://dx.doi.org/10.3389/fimmu.2022.906352 Text en Copyright © 2022 Gaißler, Meldgaard, Heeke, Babaei, Tvingsholm, Bochem, Spreuer, Amaral, Wagner, Klein, Meier, Garbe, Eigentler, Pawelec, Claassen, Weide, Hadrup and Wistuba-Hamprecht https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Gaißler, Andrea Meldgaard, Trine Sundebo Heeke, Christina Babaei, Sepideh Tvingsholm, Siri Amanda Bochem, Jonas Spreuer, Janine Amaral, Teresa Wagner, Nikolaus Benjamin Klein, Reinhild Meier, Friedegund Garbe, Claus Eigentler, Thomas K. Pawelec, Graham Claassen, Manfred Weide, Benjamin Hadrup, Sine Reker Wistuba-Hamprecht, Kilian Dynamics of Melanoma-Associated Epitope-Specific CD8+ T Cells in the Blood Correlate With Clinical Outcome Under PD-1 Blockade |
title | Dynamics of Melanoma-Associated Epitope-Specific CD8+ T Cells in the Blood Correlate With Clinical Outcome Under PD-1 Blockade |
title_full | Dynamics of Melanoma-Associated Epitope-Specific CD8+ T Cells in the Blood Correlate With Clinical Outcome Under PD-1 Blockade |
title_fullStr | Dynamics of Melanoma-Associated Epitope-Specific CD8+ T Cells in the Blood Correlate With Clinical Outcome Under PD-1 Blockade |
title_full_unstemmed | Dynamics of Melanoma-Associated Epitope-Specific CD8+ T Cells in the Blood Correlate With Clinical Outcome Under PD-1 Blockade |
title_short | Dynamics of Melanoma-Associated Epitope-Specific CD8+ T Cells in the Blood Correlate With Clinical Outcome Under PD-1 Blockade |
title_sort | dynamics of melanoma-associated epitope-specific cd8+ t cells in the blood correlate with clinical outcome under pd-1 blockade |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9300827/ https://www.ncbi.nlm.nih.gov/pubmed/35874702 http://dx.doi.org/10.3389/fimmu.2022.906352 |
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